Aminocyclohexylesters and uses thereof

ABSTRACT

Aminocyclohexylester compounds, including thioesters, are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses a variety of in vitro and in vivo uses for the compounds and compositions, including the blockade of ion channels and the treatment of arrhythmias.

This application is a division of U.S. patent application Ser. No.08/313,691, filed Sep. 27, 1994, U.S. Pat. No. 5,637,583 which is acontinuation-in-part of U.S. patent application Ser. No. 08/126,575,filed Sep. 24, 1993, abandoned.

TECHNICAL FIELD

The present invention is generally directed toward aminocyclohexylestercompounds, including thioesters, for use in cardiac arrhythmias, theblockade of ion channels and the preparation of pharmaceuticalcompositions and kits.

BACKGROUND OF THE INVENTION

Arrhythmia is a variation from the normal rhythm of the heart beat. Themajor cause of fatalities due to cardiac arrhythmias is the subtype ofarrhythmias known as ventricular fibrillation. Conservative estimatesindicate that, in the U.S. alone, approximately 300,000 individuals peryear suffer heart attacks. Approximately half of these die from suddencardiac death, the major cause of which is ventricular fibrillation.

Antiarrhythmic agents have been developed to prevent or alleviatecardiac arrhythmia. For example, Class I antiarrhythmic compounds havebeen used to treat supraventricular arrhythmias and ventriculararrhythmias. Treatment of ventricular arrhythmia is very important sincesuch an arrhythmia, especially ventricular fibrillation, can be fatal.Serious ventricular arrhythmias (ventricular tachycardia and ventricularfibrillation) occur most often in the presence of myocardial ischemiaand/or infarction. Ventricular fibrillation often occurs in the settingof acute myocardial ischemia, before infarction fully develops. Atpresent, lidocaine is the current drug of choice for prevention ofventricular fibrillation. However, many Class I antiarrhythmic compoundsmay actually increase mortality in patients who have had a myocardialinfarction. Therefore, there is a need in the art to identify newantiarrhythmic treatments, particularly treatments for ventriculararrhythmias. The present invention fulfills this need, and furtherprovides other related advantages.

SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compounds for a varietyof uses, including the blockade of ion channels in vitro and in vivo,and for the treatment of arrhythmias.

In an aspect of the present invention, aminocyclohexyl esters andthioesters are provided. In one embodiment, a compound comprises anenantiomer or geometric isomer of a compound of formula I, or a solvateor pharmaceutically acceptable salt thereof, the compound of theformula: ##STR1## wherein X is a direct bond; or --(CH₂)_(n) --Y--,where n=1, 2, or 3, and Y is a direct bond, O or S;

or --CH(R₁₂)--Y--, where R₁₂ is alkyl of from one to six carbon atoms, asaturated carbocyclic ring of from three to six carbon atoms, phenyl orbenzyl, and Y is a direct bond, O or S;

or --C(R₁₃)═CH--, where R₁₃ is hydrogen, alkyl of from one to six carbonatoms, or phenyl;

R₁ and R₂ are independently hydrogen, alkyl of three to eight carbonatoms, alkoxyalkyl of three to eight carbon atoms, or aralkyl of sevento twelve carbon atoms;

or R₁ and R₂, when taken together with the nitrogen atom to which theyare attached,

form a ring denoted by formula II: ##STR2## where m is an integer fromthree to eight, and the ring may be substituted at any one carbon atomby hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy of one tothree carbon atoms, or may be fused at two adjacent carbon atoms with anaromatic or aliphatic carbocyclic ring of six carbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring atoms, the second nitrogen being optionally substitutedwith an alkyl group of one to six carbon atoms or a phenyl ring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 3-,4-, 5-, or 6-positions, and are independently hydrogen, hydroxy, alkylof one to six carbon atoms or alkoxy of one to six carbon atoms, or arepoints of attachment of a spiro five- or six-membered heterocyclic ringcontaining one oxygen or sulfur atom; and

A is an alkyl group of five to twelve carbon atoms, or is a saturatedcarbocyclic ring of three to six carbon atoms, or is selected fromformulae III, IV, V, VI, VII or VIII: ##STR3## where R₅, R₆ and R₇ areindependently hydrogen, hydroxy, amino, fluorine, chlorine, bromine,nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of oneto six carbon atoms, or aryl, and when X is a direct bond at least oneof R₅, R₆ and R₇ is a hydroxy, fluorine, chlorine, bromine,trifluoromethyl, alkyl of from one to six carbon atoms, or arylsubstituent, and when X is --CH═CH--, and R₁ and R₂ when taken togetherwith the nitrogen atom to which they are attached, form aN-phenylpiperazine ring, and R₃ and R₄ are hydrogen, at least one of R₅,R₆ and R₇ is a substituent other than hydrogen; ##STR4## where R₈ and R₉are independently hydrogen, hydroxy, fluorine, chlorine, bromine, alkylof one to six carbon atoms, alkoxy of one to six carbon atoms or aryl;##STR5## where R₈ and R₉ are defined as above; ##STR6## where R₁₀ ishydrogen, hydroxy, fluorine, chlorine, bromine, alkyl of from one to sixcarbon atoms, alkoxy of from one to six carbon atoms, or aryl; Z is CH₂,O, S, or N--R₁₁ where R₁₁ is hydrogen or alkyl of one to six carbonatoms; ##STR7## only when X is a direct bond; ##STR8## only when X is adirect bond; with the proviso that, when X is --(CH₂)_(n) --Y--, andn=1, and Y is a direct bond, and R₁ and R₂, when taken together with thenitrogen atom to which they are attached, form a pyrrolidinyl ring, andR₃ and R₄ are hydrogen, A may not be 4-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula I, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR9## wherein Xis a direct bond; or --(CH₂)_(n) --Y--, where n=1 and Y is a directbond, O or S;

or --CH(R₁₂)--, where R₁₂ is alkyl of from one to six carbon atoms;

or --C(R₁₃)═CH--, where R₁₃ is hydrogen;

R₁ and R₂ are independently hydrogen, alkyl of three to eight carbonatoms, alkoxyalkyl of three to eight carbon atoms, or aralkyl of sevento twelve carbon atoms;

or R₁ and R₂, when taken together with the nitrogen atom to which theyare attached,

form a ring denoted by formula II: ##STR10## where m is an integer fromthree to eight, and the ring may be substituted at any one carbon atomby hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy of one tothree carbon atoms, or may be fused at two adjacent carbon atoms with anaromatic or aliphatic carbocyclic ring of six carbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring atoms, the second nitrogen being optionally substitutedwith an alkyl group of one to six carbon atoms or a phenyl ring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 3-,4-, 5-, or 6-positions, and are independently hydrogen, hydroxy, alkylof one to six carbon atoms or alkoxy of one to six carbon atoms, or arepoints of attachment of a spiro five- or six-membered heterocyclic ringcontaining one oxygen or sulfur atom; and

A is an alkyl group of five to twelve carbon atoms, or is a saturatedcarbocyclic ring of three to six carbon atoms, or is selected from:

formula III where R₅, R₆ and R₇ are independently hydrogen, hydroxy,amino, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of oneto six carbon atoms, alkoxy of one to six carbon atoms, or aryl, andwhen X is a direct bond at least one of R₅, R₆ and R₇ is a hydroxy,fluorine, chlorine, bromine, trifluoromethyl, alkyl of from one to sixcarbon atoms, or aryl substituent, and when X is --CH═CH--, and R₁ andR₂, when taken together with the nitrogen atom to which they areattached, form a N-phenylpiperazine ring, and R₃ and R₄ are hydrogen, atleast one of R₅, R₆, and R₇ is a substituent other than hydrogen;

or formula IV where R₈ and R₉ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of one to six carbon atoms, alkoxy ofone to six carbon atoms or aryl;

or formula V where R₈ and R₉ are defined as above;

or formula VI where R₁₀ is hydrogen, hydroxy, fluorine, chlorine,bromine, alkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms, or aryl; Z is CH₂, O, S, or N--R₁₁ where R₁₁ ishydrogen or alkyl of one to six carbon atoms;

or formula VII only when X is a direct bond;

or formula VIII only when X is a direct bond;

with the proviso that, when X is --(CH₂)_(n) --Y--, and n=1, and Y is adirect bond, and R₁ and R₂, when taken together with the nitrogen atomto which they are attached, form a pyrrolidinyl ring, and R₃ and R₄ arehydrogen, A may not be 4-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula I, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR11## whereinX is --(CH₂)_(n) --Y--, where n=1 and Y is a direct bond or O;

or --CH(R₁₂)--, where R₁₂ is alkyl of from one to six carbon atoms;

R₁ and R₂ are defined as in formula I as first described herein;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, alkoxy of one to sixcarbon atoms, or are points of attachment of a spiro five- orsix-membered heterocyclic ring containing one oxygen atom; and

A is an alkyl group of five to twelve carbon atoms, or is a saturatedcarbocyclic ring of three to six carbon atoms, or is selected from:

formula III where R₅, R₆ and R₇ are independently hydrogen, hydroxy,amino, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of oneto six carbon atoms, alkoxy of one to six carbon atoms, or aryl;

or formula IV where R₈ and R₉ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of one to six carbon atoms, alkoxy ofone to six carbon atoms or aryl;

or formula V where R₈ and R₉ are defined as above;

or formula VI where R₁₀ is hydrogen, hydroxy, fluorine, chlorine,bromine, alkyl of from one to six carbon atoms, alkoxy of from one tosix carbon atoms, or aryl; Z is CH₂, O, S, or N--R₁₁ where R₁₁ ishydrogen or alkyl of one to six carbon atoms;

with the proviso that, when X is --(CH₂)_(n) --Y--, and n=1, and Y is adirect bond, and R₁ and R₂, when taken together with the nitrogen atomto which they are attached, form a pyrrolidinyl ring, and R₃ and R₄ arehydrogen, A may not be 4-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula IX, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR12## whereinR₁ and R₂, when taken together with the nitrogen atom to which they areattached, either form a ring according to formula II, where m is aninteger from three to eight, and the ring may be substituted at any onecarbon atom by hydroxy, oxo, alkyl of one to three carbon atoms oralkoxy of one to three carbon atoms, or may be fused at two adjacentcarbon atoms with an aromatic or aliphatic carbocyclic ring of sixcarbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring forming atoms, the second nitrogen being optionallysubstituted with an alkyl group of one to six carbon atoms or a phenylring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, methoxy, or are pointsof attachment of a five-membered oxaspiran ring; and

A is a saturated carbocyclic ring of three to six carbon atoms, or isselected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, and at least one ofR₆ and R₇ is a substituent other than hydrogen;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is CH₂, O, S, or N--R₁₁ whereR₁₁ is hydrogen or methyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula X, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR13## whereinR₁ and R₂, when taken together with the nitrogen atom to which they areattached, form a ring denoted as in formula II, where m is an integerfrom three to eight, and the ring may be substituted at any one carbonatom by hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy ofone to three carbon atoms, or may be fused at two adjacent carbon atomswith an aromatic or aliphatic carbocyclic ring of six carbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring atoms, the second nitrogen being optionally substitutedwith an alkyl group of one to six carbon atoms or a phenyl ring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, methoxy, or are pointsof attachment of a five-membered oxaspiran ring; and

A is a saturated carbocyclic ring of from three to six carbon atoms, oris selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, and at least one ofR₆ and R₇ is a substituent other than hydrogen;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is CH₂, O, S, or N--R₁₁ whereR₁₁ is hydrogen or methyl;

with the proviso that when R₁ and R₂, taken together with the nitrogenatom to which they are attached, form a pyrrolidinyl ring, and R₃ and R₄are hydrogen, A may not be 4-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula I, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR14## whereinX is a direct bond or --CH═CH--; R₁ and R₂ are independently hydrogen,alkyl of three to eight carbon atoms, alkoxyalkyl of three to eightcarbon atoms, or aralkyl of seven to twelve carbon atoms;

or R₁ and R₂, when taken together with the nitrogen atom to which theyare attached,

form a ring denoted by formula II where m is an integer from three toeight; or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, methoxy, or are pointsof attachment of a spiro five- or six-membered heterocyclic ringcontaining one oxygen atom; and

A is a saturated carbocyclic ring of from three to six carbon atoms, oris selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, fluorine, chlorine, bromine, trifluoromethyl, methylor ethyl, and at least one of R₆ and R₇ is a substituent other thanhydrogen;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is O, S, or N--R₁₁ where R₁₁is hydrogen or methyl;

or formula VII when X is a direct bond;

or formula VIII when X is a direct bond.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XI, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR15## whereinR₁ and R₂, when taken together with the nitrogen atom to which they areattached, form a ring according to formula II where m is an integer fromthree to eight; and

A is selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, and at least one ofR₆ and R₇ is a substituent other than hydrogen;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is O or S.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XII, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR16## whereinR₁ and R₂, when taken together with the nitrogen atom to which they areattached, form a ring according to formula II where m is an integer fromthree to eight; and

A is selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, and at least one ofR₆ and R₇ is a substituent other than hydrogen;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is O or S;

with the proviso that, when R₁ and R₂ taken together with the nitrogenatom to which they are attached form a pyrrolidinyl ring, A may not be4-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XIII, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR17## whereinX is a direct bond, trans-CH═CH--, --CH₂ -- or --CH₂ --O--;

R₁ and R₂, when taken together with the nitrogen atom to which they areattached, complete a ring selected from pyrrolidinyl, piperidinyl,hexahydroazepinyl, morpholinyl, methylpiperazinyl or 3-azabicyclo3.2.2!nonanyl; and

A is selected from cyclohexyl, 3,4-dichlorophenyl, 4-bromophenyl,1-naphthyl, 2-naphthyl or 3-thianaphthenyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XIV, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR18## whereinX is a direct bond; or --(CH₂)_(n) --Y--, where n=1, 2, or 3, and Y is adirect bond, O or S;

or --CH(R₁₂)--Y--, where R₁₂ is alkyl of from one to six carbon atoms, asaturated carbocyclic ring of from three to six carbon atoms, phenyl orbenzyl, and Y is a direct bond, O or S;

or --C(R₁₃)═CH--, where R₁₃ is hydrogen, alkyl of from one to six carbonatoms, or phenyl;

R₁ and R₂ are independently hydrogen, alkyl of three to eight carbonatoms, alkoxyalkyl of three to eight carbon atoms, or aralkyl of sevento twelve carbon atoms;

or R₁ and R₂, when taken together with the nitrogen atom to which theyare attached,

form a ring denoted by formula II: ##STR19## where m is an integer fromthree to eight, and the ring may be substituted at any one carbon atomby hydroxy, oxo, alkyl of one to three carbon atoms or alkoxy of one tothree carbon atoms, or may be fused at two adjacent carbon atoms with anaromatic or aliphatic carbocyclic ring of six carbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring atoms, the second nitrogen being optionally substitutedwith an alkyl group of one to six carbon atoms or a phenyl ring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 3-,4-, 5-, or 6-positions, and are independently hydrogen, hydroxy, alkylof one to six carbon atoms or alkoxy of one to six carbon atoms, or arepoints of attachment of a spiro five- or six-membered heterocyclic ringcontaining one oxygen or sulfur atom; and

A is an alkyl group of five to twelve carbon atoms, or is a saturatedcarbocyclic ring of three to six carbon atoms, or is selected fromformulae III, IV, V, VI, VII or VIII: ##STR20## where R₅, R₆ and R₇ areindependently hydrogen, hydroxy, amino, fluorine, chlorine, bromine,nitro, trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of oneto six carbon atoms, or aryl, and when X is a direct bond at least oneof R₅, R₆ and R₇ is a substituent other than hydrogen; ##STR21## whereR₈ and R₉ are independently hydrogen, hydroxy, fluorine, chlorine,bromine, alkyl of one to six carbon atoms, alkoxy of one to six carbonatoms or aryl; ##STR22## where R₈ and R₉ are defined as above; ##STR23##where R₁₀ is hydrogen, hydroxy, fluorine, chlorine, bromine, alkyl offrom one to six carbon atoms, alkoxy of from one to six carbon atoms, oraryl; Z is CH₂, O, S, or N--R₁₁ where R₁₁ is hydrogen or alkyl of one tosix carbon atoms; ##STR24## only when X is a direct bond; ##STR25## onlywhen X is a direct bond.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XIV, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR26## whereinX is a direct bond; or --(CH₂)_(n) --Y--, where n=1, and Y is a directbond, O or S;

or --CH(R₁₂)--, where R₁₂ is alkyl of from one to six carbon atoms;

or --C(R₁₃)═CH--, where R₁₃ is hydrogen;

R₁ and R₂ are defined as in formula XIV as first described herein;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, alkoxy of one to sixcarbon atoms, or are points of attachment of a spiro five- orsix-membered heterocyclic ring containing one oxygen atom; and

A is defined as in formula XIV as first described herein.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XV, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR27## whereinX is a --CH₂ -- or --CH₂ --O--; R₁ and R₂, when taken together with thenitrogen atom to which they are attached, form a ring according toformula II, where m is an integer from three to eight, and the ring maybe substituted at any one carbon atom by hydroxy, oxo, alkyl of one tothree carbon atoms or alkoxy of one to three carbon atoms, or may befused at two adjacent carbon atoms with an aromatic or aliphaticcarbocyclic ring of six carbon atoms;

or complete a saturated monocyclic nitrogen heterocyclic ring of five toeight ring atoms, containing only carbon, nitrogen and optionally oxygenring atoms, and the heterocyclic ring containing not more than twonitrogen ring forming atoms, the second nitrogen being optionallysubstituted with an alkyl group of one to six carbon atoms or a phenylring;

or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl;

R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5-positions, and are independently hydrogen, methoxy, or are pointsof attachment of a five-membered oxaspiran ring; and

A is a saturated carbocyclic ring of from three to six carbon atoms, oris selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl,methyl, ethyl, methoxy, or ethoxy;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R₁₀ is hydrogen, and Z is CH₂, O, S, or N--R₁₁ whereR₁₁ is hydrogen or methyl.

In another embodiment, a compound comprises an enantiomer or geometricisomer of a compound of formula XVI, or a solvate or pharmaceuticallyacceptable salt thereof, the compound of the formula: ##STR28## whereinX is a --CH₂ -- or --CH₂ --O--; R₁ and R₂, when taken together with thenitrogen atom to which they are attached, form a ring according toformula II where m is an integer from three to eight; and

A is selected from:

formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, fluorine, chlorine, bromine, nitro, trifluoromethyl,methyl, ethyl, methoxy, or ethoxy;

or formula IV where R₈ and R₉ are hydrogen;

or formula V where R₈ and R₉ are hydrogen;

or formula VI where R.sub. is hydrogen, and Z is O or S.

In another aspect of the present invention, compositions are providedthat comprise an aminocyclohexyl ester or thioester compound describedabove in combination with a pharmaceutically acceptable carrier ordiluent.

The present invention, in another aspect, provides the compoundsdescribed above for use in methods for blocking ion channels in vivo andin vitro. In the in vitro embodiments, the method comprises contacting apreparation containing ion channels with an effective amount of acompound described above. In the in vivo embodiments, the methodcomprises administering to a warm-blooded animal an effective amount ofa compound described above.

In yet another aspect of the present invention, compounds includingthose described above are provided for the treatment of arrhythmia. Inthese methods, a compound is administered to a warm-blooded animal in anamount effective to treat arrhythmia.

These and other aspects of the present invention will become evidentupon reference to the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is directed toward aminocyclohexylester and thioester compounds which have a variety of uses. Such usesinclude blockade of ion channels in vitro and in vivo, and the treatmentof arrhythmias.

In one aspect, the compounds of the present invention are esters whichmay be represented by formula I: ##STR29## Compounds of formula I areaminocyclohexyl ester compounds. More specifically, theseaminocyclohexyl esters are substituted at position 2 of the cyclohexylring with an amino group, NR₁ R₂. The cyclohexyl ring may also besubstituted with additional substituents (designated as R₃ and R₄) asdescribed in more detail below. Examples of specific embodiments of theelements of compounds represented by formula I include the following.

Depending upon the selection of substituents R₁ and R₂, the compounds offormula I may be primary, secondary, or tertiary amines (i.e., where R₁and R₂ both are hydrogen, or only one is hydrogen, or neither arehydrogen, respectively). Where the amine is tertiary, it may be a cyclicamine. Amino substituents R₁ and R₂ may be independently selected fromsubstituents which include hydrogen, alkyl groups containing from threeto eight carbon atoms, alkoxyalkyl groups containing from three to eightcarbon atoms, and aralkyl groups containing from seven to twelve carbonatoms. As used herein, the term "alkyl group" refers to branched orunbranched saturated hydrocarbon fragments containing the specifiednumber of carbon atoms. Examples include n-propyl, isopropyl, andt-butyl. As used herein, the term "alkoxyalkyl" refers to alkyl groupssubstituted with alkoxy groups which in turn are alkyl groups attachedto an oxygen atom. For example, a methoxyethyl group (CH₃ OCH₂ CH₂ --)is a three carbon alkoxyalkyl group. As used herein, the term "aralkyl"refers to alkyl groups substituted with aryl groups. Aryl groups areunsubstituted aromatic groups, with phenyl and naphthyl groupspreferred. An example of an aralkyl group is the benzyl group (C₆ H₅ CH₂13 ) which is a seven carbon aralkyl group.

Alternatively, R₁ and R₂, when taken together with the amino nitrogenatom, may form a ring represented by formula II: ##STR30## where m is aninteger from three to eight. Additionally, the ring carbon atoms may bealso substituted. Suitable substituents include hydroxy, oxo (═O), alkylgroups containing from one to three carbon atoms, and alkoxy groupscontaining from one to three carbon atoms. The ring may also be fused attwo adjacent carbon atoms with a second ring. The second ring may beeither an aromatic ring preferably containing either five or six carbonatoms, or an aliphatic carbocycle preferably containing either five orsix carbon atoms. Examples of amino substituents containing a fused ringsystem as described include perhydroindolyl and1,2,3,4-tetrahydroisoquinolinyl groups.

In addition to R₁ and R₂ forming a chain of ring carbon atoms, R₁ andR₂, when taken together with the nitrogen atom to which they areattached, may complete a saturated monocyclic ring of from five to eightring atoms which includes additional heteroatoms. Preferably, R₁ and R₂,when taken together, contain only a single heteroatom. Preferredheteroatoms include nitrogen and oxygen. An example of a ring in whichR₁ and R₂ together include oxygen as a ring atom is the morpholinylgroup. An example of a ring where R₁ and R₂ together include nitrogen asa ring atom is the piperazinyl group. For cyclohexyl esters of formula Iwhich are substituted at position 2 with a heterocyclic ring containingtwo nitrogen ring atoms, the nitrogen of R₁ and R₂ (i.e., the nitrogenring atom not attached to the cyclohexyl ring) may be furthersubstituted. Suitable substituents include phenyl and alkyl groupscontaining from one to six carbon atoms. Examples of such N-phenyl orN-alkyl substitution include N-phenylpiperazinyl andN-methylpiperazinyl, respectively.

Alternatively, R₁ and R₂, when taken together with the 2-amino nitrogenof formula I, may complete a bicyclic ring. Bicyclic rings include, forexample, 3-azabicyclo 3.2.2!nonane, 2-azabicyclo 2.2.2!octane,3-azabicyclo 3.1.0!hexane, and 3-azabicyclo 3.2.0!heptane. For thesederivatives, the 2-substituents of the cyclohexyl esters of formula Iare the following groups: 3-azabicyclo 3.2.2!nonan-3-yl, 2-azabicyclo2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, and 3-azabicyclo3.2.0!heptan-3-yl.

Cyclohexane substituents R₃ and R₄ may be independently attached to ringpositions 3, 4, 5 or 6 (i.e., both R₃ and R₄ may be attached to the samering position or each attached to different ring positions). R₃ and R₄are independently selected from substituents which include hydrogen,hydroxy, alkyl groups containing from one to six carbon atoms, alkoxygroups containing from one to six carbon atoms, or points of attachmentof a spiro five- or six-membered heterocyclic ring. Preferredheterocyclic substituents contain either a single oxygen or a singlesulfur ring atom.

Depending upon the nature of X, the ester side chain, --X--A in formulaI above, may take several forms. A compound of formula I may have X as adirect bond. Alternatively, X may be an alkylene moiety, --(CH₂)_(n) --,where n=1, 2 or 3, and Y is a direct bond, an oxygen atom, or a sulfuratom; an alkylidene moiety, --CH(R₁₂)--Y--, where R₁₂ is an alkyl groupof from one to six carbon atoms, a saturated carbocyclic ring of fromthree to six carbon atoms (including cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl), a phenyl group, or a benzyl group, and Yis a direct bond, an oxygen atom, or a sulfur atom; or a cis- ortrans-alkenyl moiety, --C(R₁₃)═CH--, where R₁₃ is a hydrogen, an alkylgroup of from one to six carbon atoms, or a phenyl group. For compoundsof formula I when X is an alkenyl moiety, X is preferably atrans-alkenyl moiety.

Ester side chain component A is generally a hydrophobic moiety.Typically, a hydrophobic moiety is comprised of non-polar chemicalgroups such as hydrocarbons, hydrocarbons substituted with halogens, andethers. Suitable hydrocarbons include aliphatic and aromatichydrocarbons. Preferred aliphatic hydrocarbons include alkyl groupscontaining from five to twelve carbon atoms and carbocyclic groupscontaining from three to six carbon atoms. Preferred aromatic groupsinclude phenyl, 1-naphthyl, 2-naphthyl, indenyl (including indene whereZ, in formula VI below, is CH₂, indole where Z is N--R₁₁, benzofuranwhere Z is O, and thianaphthene where Z is S), acenaphthyl, andfluorenyl derivatives and are represented by formulae III, IV, V, VI,VII or VIII, respectively. As described below, in a preferredembodiment, Z is O, S or N--R₁₁, and in a particularly preferredembodiment Z is O or S.

Phenyl groups within the compounds of the present invention arerepresented by formula III: ##STR31## R₅, R₆, and R₇ are independentlyselected from substituents which include hydrogen, hydroxy, amino,fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl groupscontaining from one to six carbon atoms, alkoxy groups containing fromone to six carbon atoms, or aryl groups. For compounds of formula I whenX is a direct bond, at least one of R₅, R₆, and R₇ is a hydroxy,fluorine, chlorine, bromine, trifluoromethyl, alkyl of from one to sixcarbon atoms, or aryl substituent. For compounds of formula I when X isa --CH═CH--, and R₁ and R₂, when taken together with the nitrogen atomto which they are attached, form a N-phenylpiperazine ring, and R₃ andR₄ are hydrogen, at least one of R₅, R₆ and R₇ is a substituent otherthan hydrogen.

1-Naphthyl groups within the compounds of the present invention arerepresented by formula IV: ##STR32## R₈ and R₉ are independentlyselected from substituents which include hydrogen, hydroxy, fluorine,chlorine, bromine, alkyl groups containing from one to six carbon atoms,alkoxy groups containing from one to six carbon atoms, or aryl groups.

2-Naphthyl groups within the compounds of the present invention arerepresented by formula V: ##STR33## R₈ and R₉ are as defined above.

Indenyl groups of the present invention are represented by formula VI:##STR34## R₁₀ is selected from substituents which include hydrogen,hydroxy, fluorine, chlorine, bromine, an alkyl group containing from oneto six carbon atoms, an alkoxy group containing from one to six carbonatoms, or an aryl group. Z is methylene (CH₂), an oxygen atom, sulfuratom, or nitrogen atom bearing a substituent R₁₁ The indenyl groups offormula VI are derivatives of indene, indole, benzofuran, andthianaphthene when Z is methylene, nitrogen, oxygen, and sulfur,respectively. Nitrogen substituent R₁₁ may be hydrogen or an alkyl groupcontaining from one to six carbon atoms. For compounds of formula I whenX is --(CH₂)_(n) --Y--, and n=1, and Y is a direct bond, and R₁ and R₂,when taken together with the nitrogen atom to which they are attached,form a pyrrolidinyl ring, and R₃ and R₄ are hydrogen, A may not be4-thianapthenyl.

Acenaphthyl groups within the compounds of the present invention arerepresented by formula VII: ##STR35##

Fluorenyl groups within the compounds of the present invention arerepresented by formula VIII: ##STR36## Ester side chain component A maybe an acenaphthyl or fluorenyl group only when X is a direct bond. In apreferred embodiment, the acenaphthyl group is a 1-acenaphthyl group,and the fluorenyl group is a 9-fluorenyl group.

As mentioned above, the present invention provides aminocyclohexylesters represented by formula I. In a preferred embodiment, where X is--(CH₂)_(n) --Y--, n is 1. For these embodiments, Y is a direct bond, anoxygen atom, or a sulfur atom. In a particularly preferred embodiment, Yis a direct bond or an oxygen atom. In a preferred embodiment, where Xis --CH(R₁₂)--, R₁₂ is an alkyl group from one to six carbon atoms. In apreferred embodiment, where X is --C(R₁₃)═CH--, R₁₃ is a hydrogen atom.For these embodiments, R₃ and R₄ are preferably independently attachedto the cyclohexane ring at the 4- or 5- positions.

In a preferred embodiment where X is --(CH₂)_(n) --Y--, where n=1 and Yis an oxygen atom, and R₁ and R₂ are included in a ring, the presentinvention provides aminocyclohexyl esters represented by formula IX:##STR37##

In a preferred embodiment where X is --(CH₂)_(n) --Y--, where n=1 and Yis a direct bond, and R₁ and R₂ are included in a ring as describedabove, the present invention provides aminocyclohexyl esters representedby formula X: ##STR38## For either formula IX or X, R₃ and R₄ arepreferably independently attached to the cyclohexane ring at the 4- or5-positions, and are independently selected from substituents whichinclude hydrogen, methoxy, or are points of attachment of afive-membered oxaspiran ring. Similarly, for either formula IX or X, Ais preferably a saturated carbocyclic ring of from three to six carbonatoms, or is selected from: formula III where R₅ is hydrogen, and R₆ andR₇ are independently hydrogen, hydroxy, amino, fluorine, chlorine,bromine, nitro, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, andat least one of R₆ and R₇ is a substituent other than hydrogen; orformula IV where R₈ and R₉ are hydrogen; or formula V where R₈ and R₉are hydrogen; or formula VI where R₁₀ is hydrogen, and Z is CH₂, O, S,or N--R₁₁ where R₁₁ is hydrogen or methyl. However, for compoundsrepresented by formula X, when R₁ and R₂, taken together with thenitrogen atom to which they are attached, form a pyrrolidinyl ring, andR₃ and R₄ are hydrogen, A may not be 4-thianaphthenyl.

In a preferred embodiment where X is a direct bond or --CH═CH--, thepresent invention provides aminocyclohexyl esters represented by formulaI. For these embodiments, R₁ and R₂ are independently hydrogen, alkyl ofthree to eight carbon atoms, alkoxyalkyl of three to eight carbon atoms,or aralkyl of seven to twelve carbon atoms; or R₁ and R₂, when takentogether with the nitrogen atom to which they are attached, form a ringdenoted by formula II where m is an integer from three to eight; or R₁and R₂ complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl. R₃ and R₄ are independently attached tothe cyclohexane ring at the 4- or 5- positions, and are independentlyhydrogen, methoxy, or points of attachment of a spiro five- orsix-membered heterocyclic ring containing one oxygen atom. A is asaturated carbocyclic ring of from three to six carbon atoms or isselected from: formula III where R₅ is hydrogen, and R₆ and R₇ areindependently hydrogen, hydroxy, fluorine, chlorine, bromine,trifluoromethyl, methyl, and ethyl, and at least one of R₆ and R₇ is asubstituent other than hydrogen; or formula IV where R₈ and R₉ arehydrogen; or formula V where R₈ and R₉ are hydrogen; or formula VI whereR₁₀ is hydrogen, and Z is O, S, or N--R₁₁ where R₁₁ is hydrogen ormethyl; or formula VII when X is a direct bond; or formula VIII when Xis a direct bond.

In a preferred embodiment where X is --(CH₂)_(n) --Y--, where n=1 and Yis an oxygen atom, R₁ and R₂ are included in a ring, and there are no R₃and R₄, the present invention provides aminocyclohexyl estersrepresented by formula XI: ##STR39##

In a preferred embodiment where X is --(CH₂)_(n) --Y--, where n=1 and Yis a direct bond, R₁ and R₂ are included in a ring, and there are no R₃and R₄, the present invention provides aminocyclohexyl estersrepresented by formula XII: ##STR40## For either formula XI and XII, R₁and R₂ preferably are taken together with the nitrogen atom to whichthey are attached to form a ring according to formula II where m is aninteger from three to eight. Similarly, for either formula XI or XII, Ais preferably selected from: formula III where R₅ is hydrogen, and R₆and R₇ are independently hydrogen, hydroxy, amino, fluorine, chlorine,bromine, nitro, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, andat least one of R₆ and R₇ is a substituent other than hydrogen; orformula IV where R₈ and R₉ are hydrogen; or formula V where R₈ and R₉are hydrogen; or formula VI where R₁₀ is hydrogen, and Z is O or S.

In a preferred embodiment where X is selected from a direct bond;trans-C(R₁₃)═CH-- where R₁₃ is a hydrogen atom; or --(CH₂)_(n) --Y--where n=1 and Y is a direct bond or an oxygen atom, R₁ and R₂ areincluded in a ring, and there are no R₃ and R₄, the present inventionprovides aminocyclohexyl esters represented by formula XIII: ##STR41##R₁ and R₂, when taken together with the nitrogen atom to which they areattached, complete a ring selected from pyrrolidinyl, piperidinyl,hexahydroazepinyl, morpholinyl, methylpiperazinyl or 3-azabicyclo3.2.2!nonanyl. A is preferably selected from 3,4-dichlorophenyl,1-naphthyl, 2-naphthyl, cyclohexyl, 4-bromophenyl, or 3-thianaphthenyl.In a preferred embodiment, the stereochemistry is thetrans-configuration. In another preferred embodiment, thestereochemistry is the cis-configuration.

In another aspect, the compounds of the present invention areaminocyclohexyl thioesters which may be represented by formula XIV:##STR42## X, R₁, R₂, R₃, R₄ and A are defined as for formula I as firstdescribed herein, except that where X is --(CH₂)_(n) --Y--, and n=1, andY is a direct bond, and R₁ and R₂, when taken together with the nitrogenatom to which they are attached, form a pyrrolidinyl ring, and R₃ and R₄are hydrogen, A may be 4-thianaphthenyl.

In a preferred embodiment where X is selected from a direct bond;--(CH₂)_(n) --Y-- where n=1, and Y is a direct bond, an oxygen atom, ora sulfur atom; or --CH(R₁₂)-- where R₁₂ is an alkyl group of from one tosix carbon atoms; or --C(R₁₃)═CH-- where R₁₃ is hydrogen; the presentinvention provides aminocyclohexyl thioesters represented by formulaXIV. R₃ and R₄ are independently attached to the cyclohexane ring at the4- or 5-positions, and are independently hydrogen, alkoxy of from one tosix carbon atoms, or are points of attachment of a spiro five- orsix-membered heterocyclic ring containing one oxygen atom. A ispreferably an alkyl group of five to twelve carbon atoms, or is asaturated carbocyclic ring of from three to six carbon atoms, or ispreferably selected from: formula III where R₅, R₆, and R₇ areindependently hydrogen, hydroxy, amino, fluorine, chlorine, bromine,nitro, trifluoromethyl, alkyl of from one to six carbon atoms, alkoxy offrom one to six carbon atoms, or aryl, and when X is a direct bond atleast one of R₅, R₆ and R₇ is a substituent other than hydrogen; orformula IV where R₈ and R₉ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of one to six carbon atoms, alkoxy ofone to six carbon atoms, or aryl; or formula V where R₈ and R₉ areindependently hydrogen, hydroxy, fluorine, chlorine, bromine, alkyl ofone to six carbon atoms, alkoxy of one to six carbon atoms, or aryl; orformula VI where R₁₀ is independently hydrogen, hydroxy, fluorine,chlorine, bromine, alkyl of one to six carbon atoms, alkoxy of one tosix carbon atoms, or aryl; and Z is CH₂, O, S, or N--R₁₁ where R₁₁ ishydrogen or alkyl of one to six carbon atoms; or formula VII when X is adirect bond; a formula VIII when X is a direct bond.

In a preferred embodiment, where X is a --(CH₂)_(n) --Y--, and n=1, andY is a direct bond or an oxygen atom, and R₁ and R₂ are included in aring, the present invention provides aminocyclohexyl thioestersrepresented by formula XV. ##STR43## R₁ and R₂ are preferably takentogether with the nitrogen atom to which they are attached to form aring according to formula II, where m is an integer from three to eight,and the ring may be substituted at any one carbon atom by hydroxy, oxo,alkyl of one to three carbon atoms or alkoxy of one to three carbonatoms, or may be fused at two adjacent carbon atoms with an aromatic oraliphatic carbocyclic ring of five to six carbon atoms; or complete asaturated monocyclic nitrogen heterocyclic ring of five to eight ringatoms, containing only carbon, nitrogen and optionally oxygen ringatoms, and the heterocyclic ring containing not more than two nitrogenring forming atoms, wherein the second nitrogen is optionallysubstituted with an alkyl group of one to six carbon atoms or a phenylring; or complete a ring selected from 3-azabicyclo 3.2.2!nonan-3-yl,2-azabicyclo 2.2.2!octan-2-yl, 3-azabicyclo 3.1.0!hexan-3-yl, or3-azabicyclo 3.2.0!heptan-3-yl. R₃ and R₄ are independently attached tothe cyclohexane ring at the 4- or 5- positions, and are independentlyhydrogen, methoxy, or are points of attachment of a five-memberedoxaspiran ring. A is preferably a saturated carbocyclic ring of fromthree to six carbon atoms, or is preferably selected from: formula IIIwhere R₅ is hydrogen, and R₆ and R₇ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, nitro, trifluoromethyl, methyl, ethyl,methoxy, or ethoxy; or formula IV where R₈ and R₉ are hydrogen; orformula V where R₈ and R₉ are hydrogen; or formula VI where R₁₀ ishydrogen, and Z is CH₂, O, S, or N--R₁₁ where R₁₁ is hydrogen or methyl.

In a preferred embodiment where X is --(CH₂)_(n) --Y--, and n=1, and Yis a direct bond or an oxygen atom, R₁ and R₂ are included in a ring,and there are no R₃ and R₄, the present invention providesaminocyclohexyl thioesters represented by formula XVI: ##STR44## R₁ andR₂ are preferably taken together with the nitrogen atom to which theyare attached to form a ring according to formula II where m is aninteger from three to eight. A is preferably selected from: formula IIIwhere R₅ is hydrogen, and R₆ and R₇ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, nitro, trifluoromethyl, methyl, ethyl,methoxy, or ethoxy; or formula IV where R₈ and R₉ are hydrogen; orformula V where R₈ and R₉ are hydrogen; or formula VI where R₁₀ ishydrogen, and Z is O or S.

In the formulae depicted above, a bond to a substituent and/or a bondthat links A with the remainder of a compound may be shown asintersecting one or more bonds in a ring structure. This indicates thatthe substituent may be attached at any one of the carbon atoms in thering structure.

The wavy line bonds in the above formulae indicate that the substituentsat positions 1 and 2 of the cyclohexane ring may be disposed in a cis ortrans relationship. The substituents R₃ and R₄ may also be independentlyattached cis or trans to the 2-amino substituent. The compounds of thepresent invention contain at least two asymmetric carbon atoms and thusexist as enantiomers and diastereomers. Unless otherwise noted, thepresent invention includes all enantiomeric and diastereomeric forms ofthe compounds of the above formulae. Pure stereoisomers, mixtures ofenantiomers and/or diastereomers, and mixtures of different compounds ofthe above formulae are included within the present invention.

The compounds of the above formulae may be prepared using knownsynthetic methodology. In general, compounds of the present inventionare prepared by reacting the appropriate 1,2-aminocyclohexanol or1,2-aminocyclohexanethiol with an appropriate carboxylic acidderivative, derived from A--X--COOH. The carboxylic acid may beconverted to a reactive intermediate such as the acid chloride bytreatment with, for example, thionyl chloride. The reaction between theacid chloride and the alcohol or thiol is carried out in a suitablesolvent, such as chloroform. The reaction temperature may be dependentupon the nature of the reactants, however, in general, the reaction maybe refluxed. When the reaction has proceeded to substantial completion,the desired product is recovered from the reaction mixture byconventional organic chemistry techniques, and is purified generally byrecrystallisation. This reaction sequence as described generates theaminocyclohexylester as the hydrochloride salt, unless an acid scavengersuch as triethylamine is added to the mixture, in which case the productis the free base. The hydrochloride may be converted, if desired, to thefree base form by known methodologies, and subsequently, if desired, toother acid addition salts by reaction with inorganic or organic acids.Acid addition salts can also be prepared metathetically by reacting oneacid addition salt with an acid which is stronger than that of the anionof the initial salt.

Alternative routes based on known methodologies, such as those describedbelow, may be used to prepare the aminocyclohexylester compounds of thepresent invention. The carboxylic acid may be converted to analternative reactive derivative such as an activated ester, anhydride oracyl imidazole and reacted with the appropriate 1,2-aminocyclohexanol or1,2-aminocyclohexanethiol. The carboxylic acid may be reacted directlywith the aminoalcohol or aminothiol with the aid of a coupling reagentsuch as dicyclohexylcarbodiimide. The starting 1,2-aminocyclohexanol or1,2-aminocyclohexanethiol compounds are prepared by reaction sequenceswell known in the art. For example, trans-1,2-aminocyclohexanols arecommonly prepared by the ring-opening reaction of cyclohexene oxide withthe appropriate amine. The starting carboxylic acids are known or areprepared by reaction sequences well known in the art.

The synthesis procedures described herein, especially when taken withthe general knowledge in the art, provide sufficient guidance to thoseof ordinary skill in the art to perform the synthesis, isolation, andpurification of the preferred compounds described herein and otheranalogous compounds. Individual enantiomers may be obtained, if desired,from mixtures of the different forms by known methods of resolution,such as the formation of diastereomers, followed by recrystallisation.

The compounds of the above formulae may be in the form of a solvate or apharmaceutically acceptable salt, e.g., an acid addition salt. Suchsalts include hydrochloride, sulfate, phosphate, citrate, fumarate,methanesulfonate, acetate, tartrate, maleate, lactate, mandelate,salicylate, succinate and other salts known in the art.

A compound of the present invention may be prepared as a composition bycombining it with a pharmaceutically acceptable carrier or diluent.Suitable carriers or diluents include physiological saline. It will beevident to those of ordinary skill in the art that a composition of thepresent invention may contain more than one aminocyclohexyl ester and/orthioester compound.

As noted above, the present invention provides for utilizing thecompounds described above in in vitro and in vivo methods. In oneaspect, ion channels, such as cardiac sodium channels, are blocked invitro or in vivo. A preparation that contains ion channels is contactedwith, or a warm-blooded animal is administered, an effective amount ofan aminocyclohexyl ester and/or thioester compound. Suitablepreparations containing cardiac sodium channels include cells isolatedfrom cardiac tissue as well as cultured cell lines. The step ofcontacting includes, for example, incubation of ion channels with acompound under conditions and for a time sufficient to permit blockageof the channels by the compound.

In another aspect, the compounds described above are provided fortreating arrhythmia. As used herein, "treating arrhythmia" refers toboth therapy for arrhythmia and for the prevention of arrhythmiasoccurring in a heart that is susceptible to arrhythmia. An effectiveamount of a compound or composition of the present invention is used totreat arrhythmia in a warm-blooded animal, such as a human. Methods ofadministering effective amounts of antiarrhythmic agents are well knownin the art and include the administration of an oral or parenteraldosage form. Such dosage forms include, but are not limited to,parenteral solutions, tablets, capsules, sustained release implants, andtransdermal delivery systems. Generally, oral or intravenousadministration is preferred. The dosage amount and frequency areselected to create an effective level of the agent without harmfuleffects. It will generally range from a dosage of from about 0.1 toabout 100 mg/kg/day, and typically from about 0.1 to 10 mg/kg whereadministered orally or intravenously for antiarrhythmic effect.

Administration of compounds or compositions of the present invention maybe carried out in combination with the administration of other agents.For example, it may be desired to administer an opioid antagonist, suchas naloxone, if a compound exhibits opioid activity where such activitymay not be desired. The naloxone may antagonize opioid activity of theadministered compound without adverse interference with theantiarrhythmic activity.

In order to assess whether a compound has a desired pharmacologicalactivity within the present invention, it is subjected to a series oftests. In the first of such tests, a compound is given as increasing(doubling with each dose) intravenous boluses every 8 minutes to apentobarbital anesthetized rat. The effects of the compound on bloodpressure, heart rate and the ECG are measured 30 seconds, 1, 2, 4 and 8minutes after each dose. Increasing doses are given until the animaldies. The cause of death is identified as being of either respiratory orcardiac origin. This test gives an indication as to whether the compoundis blocking sodium channels and/or potassium channels, and in additiongives information about acute toxicity. The indices of sodium channelblockade are increasing P-R interval and QRS widening of the ECG.Potassium channel blockade results in Q-T interval prolongation of theECG.

A second test involves administration of a compound as an infusion topentobarbital anesthetized rats in which the left ventricle is subjectedto electrical square wave stimulation performed according to a presetprotocol described in further detail below. This protocol includes thedetermination of thresholds for induction of extrasystoles andventricular fibrillation. In addition, effects on electricalrefractoriness are assessed by a single extra beat technique. Inaddition effects on blood pressure, heart rate and the ECG are recorded.In this test, sodium channel blockers produce the ECG changes expectedfrom the first test. In addition, sodium channel blockers also raise thethresholds for induction of extrasystoles and ventricular fibrillation.Potassium channel blockade is revealed by increasing refractoriness andwidening of the Q-T intervals of the ECG.

A third test involves exposing isolated rat hearts to increasingconcentrations of a compound. Ventricular pressures, heart rate,conduction velocity and ECG are recorded in the isolated heart in thepresence of varying concentrations of the compound. This test providesevidence for direct toxic effects on the myocardium. Additionally,selectivity, potency and efficacy of action of a compound can beascertained under conditions simulating ischaemia. Concentrations foundto be effective in this test are expected to be efficacious in theelectrophysiological studies.

A fourth test is estimation of the antiarrhythmic activity of a compoundagainst the arrhythmias induced by coronary artery occlusion inanaesthetized rats. It is expected that a good antiarrhythmic compoundwill have antiarrhythmic activity at doses which have minimal effects oneither the ECG, blood pressure or heart rate under normal conditions.

A compound is also tested directly for effects on sodium and potassiumcurrents in isolated rat myocytes. Isolated rat myocytes are obtained inthe conventional manner from isolated hearts. They are used in voltageclamp studies. In order to obtain adequate voltage clamps for estimationof a compound's effects on sodium and potassium currents, the whole-cellpatch clamp technique is used. In this technique, a microelectrode isattached to a cell in such a manner that the cell's internal contentsare in free communication with the electrode's content. Using theappropriate buffers and conventional voltage step protocols, both sodiumand potassium currents can be identified. The activity of a compound istested on these currents.

All of the foregoing tests are performed using rat tissue. In order toensure that a compound is not having effects which are only specific torat tissue, further experiments are performed in dogs and primates. Inorder to assess possible sodium channel and potassium channel blockingactions in vivo in dogs, a compound is tested for effects on the ECG,ventricular epicardial conduction velocity and responses to electricalstimulation. An anesthetized dog is subjected to an open chest procedureto expose the left ventricular epicardium. After the pericardium isremoved from the heart a recording/stimulation electrode is sewn ontothe epicardial surface of the left ventricle. Using this array, andsuitable stimulation protocols, conduction velocity across theepicardium as well as responsiveness to electrical stimulation can beassessed. This information coupled with measurements of the ECG allowsone to assess whether sodium and/or potassium channel blockade occurs.As in the first test in rats, a compound is given as a series ofincreasing bolus doses. At the same time possible toxic effects of acompound on the dog's cardiovascular system is assessed.

The effects of a compound on the ECG and responses to electricalstimulation are also assessed in intact, halothane anesthetized baboons(Papio anubis). In this preparation, a blood pressure cannula and ECGelectrodes are suitably placed in an anesthetized baboon. In addition, astimulating electrode is placed into the right ventricle, together witha monophasic action potential electrode. As in the tests describedabove, ECG and electrical stimulation responses to a compound reveal thepossible presence of sodium and/or potassium channel blockade. Themonophasic action potential also reveals whether a compound widens theaction potential, an action expected of a potassium channel blocker.

The present invention also provides kits that contain a pharmaceuticalcomposition which includes one or more compounds of the above formulae.The kit also includes instructions for the use of the pharmaceuticalcomposition for the blocking of ion channels or for the treatment ofarrhythmia. Preferably, a commercial package will contain one or moreunit doses of the pharmaceutical composition. For example, such a unitdose may be an amount sufficient for the preparation of an intravenousinjection. It will be evident to those of ordinary skill in the art thatcompounds which are light and/or air sensitive may require specialpackaging and/or formulation. For example, packaging may be used whichis opaque to light, and/or sealed from contact with ambient air, and/orformulated with suitable coatings or excipients.

The following examples are offered by way of illustration and not by wayof limitation.

EXAMPLES Example 1 (±)-trans-2-(1-pyrrolidinyl)cyclohexyl!(3,4-dichlorophenoxy)acetatemonohydrochloride (Compound #1)

(i) Pyrrolidine (10.5 g, 148 mmol), cyclohexene oxide (15 mL, 148 mmol)and water (5 mL) are refluxed under nitrogen until GC or tlc analysisshows the reaction to be complete. The cooled mixture is partitionedbetween saturated sodium hydroxide solution (150 mL) and ether (150 mL).The aqueous layer is washed with additional ether (75 mL) and thecombined ether layers are dried over sodium sulfate. The ether isremoved in vacuo to leave the crude aminoalcohol (26 g), which is vacuumdistilled (bp 51° C. at full vacuum) to give (±)-trans-2-(1-pyrrolidinyl)!cyclohexanol.

(ii) 3,4-Dichlorophenoxyacetic acid (2.62 g, 12 mmol) is refluxed inthionyl chloride (10 mL) under nitrogen for 1 hour. After stirring atroom temperature for a further hour, the thionyl chloride is removed invacuo to leave an orange oil, which is dissolved in chloroform (10 mL).The acid chloride solution is refluxed for 12 hours with a solution of(±)-trans- 2-(1-pyrrolidinyl)!cyclohexanol (2 g, 12 mmol) in chloroform(5 mL) under nitrogen. Ether (40 mL) is added to the cooled mixture, themixture is stirred for 30 min., and the crude product is filtered off(3.61 g) and washed with ether. It is recrystallised from the minimumvolume of hot methanol/ether to yield the title compound.

Example 2 (±)-trans- 2-(1-pyrrolidinyl)cyclohexyl!(1-naphthoxy)acetatemonohydrochloride (Compound #2)

The title compound is prepared according to the method described inExample 1(ii), using 1-naphthoxyacetic acid (2.4 g, 12 mmol) to preparethe acid chloride as a yellow solid, which is dissolved in chloroform(25 mL). This solution is added to a solution of (±)-trans-2-(1-pyrrolidinyl)!cyclohexanol prepared as in Example 1(i) (2 g, 12mmol) in chloroform (5 mL) under nitrogen. The mixture is refluxed for10 hours. All solvent is removed in vacuo. The resulting solid is mixedwith hot ethyl acetate (100 mL) and methanol is added until itdissolves. On cooling, the solid is collected and washed with ethylacetate, and recrystallised from hot methanol/ethyl acetate to give thetitle compound.

Example 3 (±)-trans-{2- N-(3-azabicyclo3.2.2!nonyl)!cyclohexyl}(3,4-dichlorophenoxy)acetate monohydrochloride(Compound #3)

(i) (±)-trans-{2- N-(3-Azabicyclo 3.2.2!nonyl)!}cyclohexanol is preparedaccording to the method described in Example 1(i) by refluxing3-azabicyclo 3.2.2!nonane (5 g, 40 mmol), cyclohexene oxide (3.9 mL, 40mmol) and water (3 mL) for 5 hours. The crude product, a waxy yellowishsolid obtained on removal of ether, is used without furtherpurification.

(ii) A chloroform solution (15 mL) of 3,4-dichlorophenoxyacetylchloride, prepared from 3,4-dichlorophenoxyacetic acid (2 g, 9 mmol) asin Example 1(ii), is added to a solution of (±)-trans-{2-N-(3-azabicyclo 3.2.2!nonyl)!}cyclohexanol (2 g, 9 mmol) in chloroform(7 mL) under nitrogen. The mixture is refluxed for 12 hours. Ether (30mL) is added to the cooled mixture, and the crude product is filteredoff and washed with ether. It is recrystallised from the minimum volumeof hot ethyl acetate to yield the title compound.

Example 4 (±)-trans-2-(4-morpholinyl)cyclohexyl!(3,4-dichlorophenoxy)acetatemonohydrochloride (Compound #4)

(i) (±)-trans- 2-(4-Morpholinyl)!cyclohexanol is prepared by the methoddetailed in Example 1(i), refluxing morpholine (5 g, 57 mmol),cyclohexene oxide (5.8 mL, 57 mmol) and water (3 mL) for 2 hours. Thecrude product is purified by full vacuum distillation (bp 75°-80° C.).

(ii) A chloroform solution (10 mL) of 3,4-dichlorophenoxyacetylchloride, prepared from 3,4-dichlorophenoxyacetic acid (2.4 g, 11 mmol)as in Example 1(ii), is added to a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2 g, 11 mmol) in chloroform (5 mL) undernitrogen. The mixture is refluxed for 8 hours. The crude product isfiltered off and washed with ether. More ether may be added to thefiltrate to yield further crude product. The product is recrystallisedfrom hot methanol to give the title compound.

Example 5 (±)-trans-2-(1-hexahydroazepinyl)cyclohexyl!(3,4-dichlorophenoxy)acetatemonohydrochloride (Compound #5)

(i) (±)-trans- 2-(1-Hexahydroazepinyl)!cyclohexanol is prepared by themethod detailed in Example 1(i), refluxing hexamethyleneimine (17.3 mL,0.15 mol), cyclohexene oxide (15.5 mL, 0.15 mol) and water (5 mL). Theproduct is purified by full vacuum distillation (bp 62°-65° C.).

(ii) A chloroform solution (10 mL) of 3,4-dichlorophenoxyacetylchloride, prepared from 3,4-dichlorophenoxyacetic acid (2.36 g, 11 mmol)as in Example 1(ii), is added to a solution of (±)-trans-2-(1-hexahydroazepinyl)!cyclohexanol (2 g, 10 mmol) in chloroform (5 mL)under nitrogen. The mixture is refluxed for 10 hours. The crude productwhich precipitates on adding ether to the mixture, is filtered off andwashed with ether. It is recrystallised from hot methanol (4 mL), andwashed with ether, to give the title compound.

Example 6 (±)-trans- 2-(4-morpholinyl)cyclohexyl!benzob!thiophene-3-acetate monohydrochloride (Compound #6)

3-Thianaphtheneacetic acid (4.81 g, 25 mmol) is refluxed in thionylchloride (16 mL) under nitrogen for 1 hour. After stirring at roomtemperature for a further 20 min., the thionyl chloride is removed invacuo to leave a brown oil, which is dissolved in chloroform (10 mL).The acid chloride solution is added to a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol prepared as in Example 4(i) (4.5 g, 24.3mmol) in chloroform (5 mL) under nitrogen. The mixture is refluxed for11 hours. Ether (25 mL) is added to the cooled mixture and the crudeproduct is filtered off and washed with ether (3×10 mL). The product maybe recrystallised from hot methanol/ether to give the title compound.

Example 7 (±)-trans- 2-(1-pyrrolidinyl)cyclohexyl!(cyclohexyl)acetatemonohydrochloride (Compound #7)

The title compound is prepared according to the method described inExample 1(ii), using cyclohexylacetic acid (4.4 g, 31 mmol) to preparethe acid chloride as a pale yellow oil, which is dissolved in chloroform(10 mL). This solution is added to a solution of (±)-trans-2-(1-pyrrolidinyl)!cyclohexanol prepared as in Example 1(i) (5 g, 30mmol) in chloroform (10 mL) under nitrogen. The mixture is refluxed for15 hours. The solvent is removed in vacuo to leave a solid. The crudeproduct may be recrystallised from hot ethyl acetate or methanol/diethylether to give the title compound.

Example 8 (±)-trans- 2-(4-morpholinyl)cyclohexyl!naphthyl-1-acetatemonohydrochloride (Compound #8)

1-Naphthylacetic acid (5.30 g, 28.5 mmol) is refluxed in thionylchloride (10 mL) under nitrogen for 1 hour. After stirring at roomtemperature for a further 90 min., the thionyl chloride is removed invacuo to leave an orange-brown oil, which is dissolved in chloroform (10mL). The acid chloride solution is slowly added to a solution of(±)-trans- 2-(4-morpholinyl)!cyclohexanol prepared as in Example 4(i)(5.0 g, 27 mmol) in chloroform (15 mL) under nitrogen. The mixture isrefluxed for 5 hours. The solvent is removed in vacuo, and the residueis partitioned between 1M hydrochloric acid (150 mL) and ether (100 mL).The ether layer is separated and the aqueous is washed with more ether(2×50 mL), and then basified by the addition of 50% sodium hydroxidesolution. This is then extracted with ether (3×50 mL), and the combinedether extracts are washed with water until GC shows no unreactedaminoalcohol in the ether. The ether containing the product is thendried over sodium sulfate, and the solvent is removed to leave the crudefree ester. The residue is dissolved in ether (40 mL) anddichloromethane (5 mL) and treated with HCl in ether to precipitate thesalt. It is washed with ether and recrystallised from ethylacetate/methanol to yield the title compound.

Example 9 (±)-trans- 2-(4-morpholinyl)cyclohexyl!naphthyl-2-acetatemonohydrochloride (Compound #9)

2-Naphthylacetyl chloride is prepared according to the method describedin Example 8 using 2-naphthylacetic acid (2.64 g, 14.2 mmol) to give thecorresponding acid chloride as a yellow solid which is dissolved inchloroform (10 mL). The solution is refluxed for 9 hours with a solutionof (±)-trans- 2-(4-morpholinyl)!cyclohexanol (2.5 g, 13.5 mmol) inchloroform (10 mL) under nitrogen. The solvent is removed in vacuo, andthe residue is partitioned between 1M sodium hydroxide solution (100 mL)and dichloromethane (80 mL). The organic layer is separated and theaqueous is washed with more dichloromethane (2×75 mL). The combineddichloromethane extracts are dried over sodium sulfate, and the solventis removed to leave the crude free ester. This may be purified by columnchromatography using silica gel and chloroform/ethyl acetate (3:1) aseluent. The free ester is converted to the salt by treatment with HCl inether/dichloromethane (3:1). The resulting solid is washed with etherand recrystallised from hot methanol to yield the title compound.

Example 10 (±)-trans- 2-(4-morpholinyl)cyclohexyl!phenylacetatemonohydrochloride (Compound #10)

Phenylacetyl chloride is prepared according to the method described inExample 8 using phenylacetic acid (2.13 g, 15.6 mmol) to give a paleyellow oil which is dissolved in chloroform (10 mL). This solution isrefluxed for 12 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2.75 g, 14.9 mmol) in chloroform (10 mL)under nitrogen. The reaction mixture is partitioned between 1M sodiumhydroxide solution (100 mL) and dichloromethane (80 mL). The organiclayer is separated and the aqueous is washed with more dichloromethane(2×50 mL). The combined dichloromethane extracts are dried over sodiumsulfate, and the solvent is removed to leave the crude free ester. Thisis purified by column chromatography and converted to the hydrochloridesalt as described in Example 9. The product is recrystallised from hotmethanol to yield the title compound.

Example 11 (±)-trans-2-(4-morpholinyl)cyclohexyl!(3,4-dichlorophenyl)acetatemonohydrochloride (Compound #11)

3,4-Dichlorophenylacetyl chloride is prepared according to the methoddescribed in Example 8, using 3,4-dichlorophenylacetic acid (2.62 g,12.8 mmol) to give a yellow oil which is dissolved in chloroform (15mL). This solution is refluxed for 9 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL)under nitrogen. The solvent is removed in vacuo, and the residue ispartitioned between 1M hydrochloric acid (75 mL) and ether (75 mL). Theether layer is separated and the aqueous is washed with more ether (2×30mL), and then basified to pH14 by the addition of 50% sodium hydroxidesolution. This is then extracted with ether (4×30 mL), and the combinedether extracts are washed with water until GC shows no unreactedaminoalcohol in the ether. The ether containing the product is thendried over sodium sulfate, and the solvent is removed to leave the crudefree ester. The residue is dissolved in ether (20 mL) and treated withHCl in ether to precipitate the salt. It is washed with ether andrecrystallised from hot methanol to yield the title compound.

Example 12 (±)-trans- 2-(4-morpholinyl)cyclohexyl!(4-nitrophenyl)acetatemonohydrochloride (Compound #12)

4-Nitrophenylacetyl chloride, prepared according to the method describedin Example 8 using 4-nitrophenylacetic acid (5.4 g, 29.8 mmol), isdissolved in chloroform (15 mL). This solution is refluxed for 9 hourswith a solution of (±)-trans- 2-(4-morpholinyl)!cyclohexanol (5.25 g,28.3 mmol) in chloroform (15 mL) under nitrogen. The solvent is removedin vacuo, and the residue is partitioned between 1M hydrochloric acid(60 mL) and ether (50 mL). The ether layer is separated and the aqueouslayer is washed with more ether (2×50 mL), and then basified by theaddition of 50% sodium hydroxide solution. This is then extracted withether (5×60 mL), and the combined ether extracts are washed repeatedlywith water to remove any unreacted aminoalcohol. The ether containingthe product is then dried over sodium sulfate, and the solvent isremoved to leave the crude free ester. The residue is dissolved in ether(20 mL) and treated with HCl in ether to precipitate the salt. It iswashed with ether and recrystallised from hot methanol to yield thetitle compound.

Example 13 (±)-trans-2-(4-methyl-1-piperazinyl)cyclohexyl!naphthyl-2-acetate dihydrochloride(Compound #13)

(i) (±)-trans- 2-(4-Methyl-1-piperazinyl)!cyclohexanol is prepared bythe method detailed in Example 1(i), refluxing 1-methylpiperazine (16.6mL, 150 mmol), cyclohexene oxide (15.2 mL, 150 mmol) and water (5 mL)for 5 hours. The crude product is purified by full vacuum distillation(bp 94° C.) to give a white solid.

(ii) 2-Naphthylacetyl chloride is prepared according to the methoddescribed in Example 8 using 2-naphthylacetic acid (2.47 g, 13.3 mmol)to give a yellow solid which is dissolved in chloroform (15 mL). Thissolution is added to a solution of (±)-trans-2-(4-methyl-1-piperazinyl)!cyclohexanol (2.5 g, 12.6 mmol) in chloroform(10 mL), and the mixture is refluxed for 11 hours under nitrogen. Thesolvent is removed in vacuo, and the residue is partitioned between 1Mhydrochloric acid (100 mL) and ether (60 mL). The ether layer isseparated and the aqueous is washed with more ether (2×30 mL), and thenbasified by the addition of 50% sodium hydroxide solution. This is thenextracted with ether (4×30 mL), and the combined ether extracts arewashed repeatedly with water to remove any unreacted aminoalcohol. Theether containing the product is then dried over sodium sulfate, and thesolvent is removed to leave the crude free ester. The free ester isdissolved in ether/dichloromethane (35 mL, 4:3) and converted to thedihydrochloride salt by treatment with an excess of HCl in the samesolvent. The resulting solid is washed with ether and recrystallisedfrom hot methanol to yield the title compound.

Example 14 (±)-trans-2-(4-methyl-1-piperazinyl)cyclohexyl!naphthyl-1-acetatemonohydrochloride (Compound #14)

1-Naphthylacetyl chloride is prepared according to the method describedin Example 8 using 1-naphthylacetic acid (2.47 g, 13.3 mmol) to give ayellow oil which is dissolved in chloroform (10 mL). This solution isadded to a solution of (±)-trans-2-(4-methyl-1-piperazinyl)!cyclohexanol (2.5 g, 12.6 mmol) in chloroform(10 mL), and the mixture is refluxed for 11 hours under nitrogen. Thecrude free ester is isolated as described in Example 13, and isconverted to the monohydrochloride salt in ether/dichloromethane (35 mL,6:1) by treatment with 1 equivalent of HCl in the same solvent. Theresulting solid is washed with ether and recrystallised from hot ethylacetate/methanol to yield the title compound.

Example 15 (±)-trans- 2-(4-morpholinyl)cyclohexyl!-1-naphthoatemonohydrochloride (Compound #15)

1-Naphthoyl chloride, prepared according to the method described inExample 8 using 1-naphthoic acid (2.44 g, 14.2 mmol), is dissolved inchloroform (15 mL). This solution is refluxed for 60 hours with asolution of (±)-trans- 2-(4-morpholinyl)!cyclohexanol (2.5 g, 13.5 mmol)in chloroform (12 mL) under nitrogen. The solvent is removed in vacuo,and the residue is treated as in Example 13 to give the crude freeester. This is purified by column chromatography using silica gel andchloroform/ethyl acetate (9:1) as eluent. The free ester is converted tothe salt by treatment with HCl in ether. The resulting solid is washedwith ether and recrystallised from hot ethyl acetate/methanol to yieldthe title compound.

Example 16 (±)-trans- 2-(4-morpholinyl)cyclohexyl!benzob!thiophene-4-acetate monohydrochloride (Compound #16)

4-Thianaphtheneacetyl chloride is prepared according to the methoddescribed in Example 8 using 4-thianaphtheneacetic acid (2.44 g, 12.8mmol) to give a red-brown oil which is dissolved in chloroform (15 mL).This solution is refluxed for 27 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2.27 g, 13.5 mmol) in chloroform (10 mL)under nitrogen. The solvent is removed in vacuo, and the residue istreated as in Example 13 to give the crude free ester. This is purifiedby column chromatography using silica gel and chloroform/ethyl acetate(9:1) as eluent. The free ester is converted to the salt by treatmentwith HCl in ether. The resulting solid is washed with ether andrecrystallised from hot methanol to yield the title compound.

Example 17 (±)-trans- 2-(4-morpholinyl)cyclohexyl!(4-bromophenyl)acetatemonohydrochloride (Compound #17)

4-Bromophenylacetyl chloride is prepared according to the methoddescribed in Example 8 using 4-bromophenylacetic acid (2.75 g, 12.8mmol) to give an oil which is dissolved in chloroform (10 mL). Thissolution is refluxed for 19 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2.25 g, 12.2 mmol) in chloroform (10 mL)under nitrogen. The solvent is removed in vacuo, and the residue istreated as in Example 13 to give the crude free ester, which is thendissolved in 1M hydrochloric acid (70 mL). Sodium chloride (14 g) isadded to the solution which is then extracted with chloroform (60 mLthen 2×40 mL). The combined extracts are dried over sodium sulfate andthe solvent removed in vacuo. The residue is recrystallised from hotethyl acetate/methanol to give the title compound.

Example 18 (±)-trans- 2-(4-morpholinyl)cyclohexyl!-3,4-dichlorocinnamatemonohydrochloride (Compound #18)

3,4-Dichlorocinnamyl chloride is prepared according to the methoddescribed in Example 8 using 3,4-dichlorocinnamic acid (2.46 g, 11.4mmol) to give an oil which is dissolved in chloroform (10 mL). Thissolution is refluxed for 35 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol (2.0 g, 10.8 mmol) in chloroform (10 mL)under nitrogen. The solvent is removed in vacuo and the residuepartitioned between 10% aqueous sodium hydroxide (50 mL) anddichloromethane (50 mL). The aqueous layer is extracted with moredichloromethane (2×50 mL) and the combined extracts are dried oversodium sulfate. The solvent is removed and the crude ester is purifiedby column chromatography using silica gel and chloroform/ethyl acetate(1:1) as eluent. The free ester is converted to the salt by treatmentwith HCl in dichloromethane/ether (1:4). The resulting solid is washedwith ether and recrystallised from hot methanol to yield the titlecompound.

Example 19 (±)-trans- 2-(1-piperidinyl)cyclohexyl!thiophenoxyacetatemonohydrochloride (Compound #19)

(i) (±)-trans- 2-(1-Piperidinyl)!cyclohexanol is prepared by the methoddetailed in Example 1(i), refluxing piperidine (14.8 mL, 0.15 mol),cyclohexene oxide (15.5 mL, 0.15 mol) and water (5 mL). The product ispurified by full vacuum distillation to give a colorless liquid.

(ii) A chloroform (10 mL) solution of thiophenoxyacetyl chloride,prepared from thiophenoxyacetic acid (1.85 g, 11 mmol) as in Example 8,is refluxed for 12 hours with a solution of (±)-trans-2-(1-piperidinyl)!cyclohexanol (1.85 g, 10 mmol) in chloroform (15 mL)under nitrogen. The crude product, which precipitates on cooling themixture, is filtered off and washed with ether. It is recrystallisedfrom hot methanol (4 mL), and washed with ether, to give the titlecompound.

Example 20 (±)-trans-2-(4-morpholinyl)cyclohexyl!-2-(1-naphthyl)propionate monohydrochloride(Compound #20)

(i) 1-Naphthylacetic acid (10 g, 53.7 mmol) is dissolved in dry THF (150mL) under nitrogen. The solution is cooled to -10° C., treated with 1.6Mbutyl lithium in hexanes (72 mL, 115 mmol), and stirred for 15 minutes.A solution of iodomethane (3.7 mL, 59.4 mmol) in dry THF (50 mL) isadded, and the mixture is allowed to warm to room temperature and stirfor several hours. The solvent is removed in vacuo, and the residuedissolved in 5% sodium hydroxide solution (500 mL), washed with ether(3×200 mL), and then acidified by the addition of 6N hydrochloric acid.The aqueous is then extracted with dichloromethane (3×200 mL), theorganic extracts are dried over sodium sulfate, and the solvent removedto leave 2-(1-naphthyl)propionic acid as a white solid.

(ii) 2-(1-Naphthyl)propionyl chloride, prepared according to the methoddescribed in Example 8 using 2-(1-napthyl)propionic acid (2.55 g, 12.8mmol), is dissolved in chloroform (10 mL). The acid chloride solution isadded to a solution of (±)-trans- 2-(4-morpholinyl)!cyclohexanolprepared as in Example 4(i) (2.25 g, 12.2 mmol) in chloroform (10 mL)under nitrogen. The mixture is refluxed for 14 hours. The solvent isremoved in vacuo, and the residue is partitioned between 1M hydrochloricacid (150 mL) and ether (100 mL). The ether layer is separated and theaqueous is washed with more ether (2×50 mL), and then basified by theaddition of 50% sodium hydroxide solution. This is then extracted withether (3×50 mL), and the combined ether extracts are washed with wateruntil GC shows no unreacted aminoalcohol in the ether. The ethercontaining the product is then dried over sodium sulfate, and thesolvent is removed to leave the crude free ester. The residue isdissolved in ether (40 mL) and dichloromethane (5 mL) and treated withHCl in ether to precipitate the salt. It is washed with ether andrecrystallised from ethyl acetate/methanol to yield the title compound.

Example 21 (±)-(1α,2β,4β,5β)-4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl!benzofuran-2-acetatemonohydrochloride (Compound #21)

(i) Iodine (122 g, 480 mmol) is added gradually over 5 hours to amixture of 1,4-cyclohexadiene (77 g, 963 mmol) and sodium iodate (51.5g, 240 mmol) in glacial acetic acid (50 mL). This mixture is stirred fora further 1 hour and then water (17.3 g, 963 mmol) and potassium acetate(94.3 g, 963 mmol) are added and the mixture is refluxed for 3 hours.The acetic acid is removed by vacuum distillation, and the residue isdissolved in ether (400 mL) and washed with saturated sodiummetabisulfite solution (400 mL). The aqueous layer is extracted withethyl acetate (3×80 mL), and the combined organic extracts are driedover sodium sulfate and the solvent removed. The resulting oil isdissolved in ether (200 mL) and treated with 10% potassium hydroxide inmethanol until chromatography shows the conversion tocis-4,5-cyclohexenediol to be complete. The mixture is neutralized bythe addition of solid carbon dioxide. The solvent is removed and theproduct is partitioned between saturated sodium chloride solution andethyl acetate. The ethyl acetate extracts are dried over sodium sulfate,the solvent is removed and the product, cis-4,5-cyclohexenediol, ispurified by vacuum distillation (bp 90°-100° C. at full vacuum) to givea white solid.

(ii) A solution of the diol (37.1 g, 325 mmol) in dry THF (600 mL) isadded over 1 hour to a cooled, stirred suspension of sodium hydride (32g of a 60% dispersion in mineral oil, 800 mmol) in dry THF (800 mL)under nitrogen. A solution of methyl iodide (60 mL, 964 mmol) in THF (60mL) is added and the mixture stirred for 12 hours. The reaction isquenched by the addition of moist ether followed by water. The solventis removed and the residue partitioned between water (200 mL) and ether(300 mL). The aqueous layer is extracted with additional ether (2×75 mL)and the combined organic extracts are dried over sodium sulfate and thesolvent removed. The product, 4,5-dimethoxycyclohexene, is purified byvacuum distillation (bp 90° C. at 20 mmHg) to give a colorless oil.

(iii) m-Chloroperbenzoic acid (43 g, 250 mmol) is dissolved in ether(400 mL), any aqueous layer is separated, and the ether solution isdried over sodium sulfate and added quickly dropwise to a solution of4,5-dimethoxycyclohexene (17.7 g, 125 mmol) in ether (250 mL). Themixture is stirred for 12 hours, most of the ether is removed (450 mL)in vacuo, and dichloromethane is added (400 mL). The solution is washedwith 20% sodium metabisulfite solution (3×200 mL), saturated sodiumbicarbonate solution (3×200 mL) and brine (3×200 mL). The solvent isremoved and the epoxide is refluxed with pyrrolidine (40 mL, 480 mmol)and water (10 mL) for 2 hours. After cooling, 25% sodium hydroxidesolution (30 mL) is added and the excess pyrrolidine removed bydistillation. The product, 4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexanol,is extracted into dichloromethane (3×100 mL) and purified bydistillation (bp 90°-100° C. at full vacuum).

(iv) Benzofuran-2-acetyl chloride, prepared according to the methoddescribed in Example 8 using benzofuran-2-acetic acid (2.1 g, 12 mmol),is dissolved in chloroform (15 mL). This solution is added to a solutionof 4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexanol (2.5 g, 11 mmol) inchloroform (10 mL), and the mixture is refluxed for 11 hours undernitrogen. The solvent is removed in vacuo, and the residue ispartitioned between 1M hydrochloric acid (100 mL) and ether (60 mL). Theether layer is separated and the aqueous is washed with more ether (2×30mL), and then basified by the addition of 50% sodium hydroxide solution.This is then extracted with ether (4×30 mL), and the combined etherextracts are washed repeatedly with water to remove any unreactedaminoalcohol. The ether containing the product is then dried over sodiumsulfate, and the solvent is removed to leave the crude free ester. Thefree ester is converted to the hydrochloride salt by treatment with HClin ether. The resulting solid is washed with ether and recrystallisedfrom hot methanol to yield the title compound.

Example 22 (±)-trans-{2-bis(2-methoxyethyl)amino!cyclohexyl}fluorene-9-carboxylatemonohydrochloride (Compound #22)

(i) The intermediate aminoalcohol, (±)-trans-{2-bis(2-methoxyethyl)amino!}cyclohexanol, is prepared by the methoddetailed in Example 1 (i), refluxing bis(2-methoxyethyl)amine (25 mL,169 mol), cyclohexene oxide (17.2 mL, 170 mmol) and water (8 mL) for 30hours. The crude product is purified by full vacuum distillation (bp83°-85° C.) to give a clear liquid.

(ii) 9-Fluorenecarboxylic acid (2.43 g, 11.5 mmol) is converted to thecorresponding acid chloride according to the method described in Example8. The resulting white solid is dissolved in chloroform (10 mL) andrefluxed under nitrogen with a chloroform solution (10 mL) of(±)-trans-{2- bis(2-methoxyethyl)amino!}cyclohexanol (2.7 g, 11 mmol)for 20 hours. The solvent is removed in vacuo, and the residue ispartitioned between 1M hydrochloric acid (100 mL) and ether (100 mL).The ether layer is separated and the aqueous is washed with more ether(2×50 mL), and then basified by the addition of 50% sodium hydroxidesolution. This is then extracted with ether (4×40 mL), and the combinedether extracts are washed repeatedly with water to remove any unreactedaminoalcohol. The ether containing the product is then dried over sodiumsulfate, and the solvent is removed to leave the crude free ester. Thefree ester is converted to the hydrochloride salt by treatment with HClin ether. The resulting solid is washed with ether and recrystallisedfrom hot methanol to yield the title compound.

Example 23 S-{(±)-trans-2-(4-morpholinyl)cyclohexyl!}(3,4-dimethoxyphenyl)thioacetatemonohydrochloride (Compound #23)

(i) Morpholine (7.6 g, 87 mmol), cyclohexene sulfide (10 g, 88 mmol) andwater (5 mL) are refluxed under nitrogen for 5 hours or until GC or tlcanalysis show the reaction to be complete. The cooled mixture ispartitioned between saturated sodium hydroxide solution (150 mL) anddichloromethane (150 mL). The aqueous layer is washed withdichloromethane (2×50 mL) and the combined organic layers are dried oversodium sulfate. The solvent is removed in vacuo to give (±)-trans-2-(4-morpholinyl)!cyclohexanethiol which is purified by full vacuumdistillation (bp 90°-100° C.).

(ii) (3,4-dimethoxyphenyl)acetyl chloride is prepared according to themethod described in Example 8 using 3,4-dimethoxyphenylacetic acid (2.85g, 14.5 mmol) to give a brown oil which is dissolved in chloroform (10mL). This solution is refluxed for 3 hours with a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanethiol (2.8 g, 14 mmol) in chloroform (10mL) under nitrogen. The reaction mixture is partitioned between 1Msodium hydroxide solution (100 mL) and dichloromethane (80 mL). Theorganic layer is separated and the aqueous is washed with moredichloromethane (2×50 mL). The combined dichloromethane extracts aredried over sodium sulfate, and the solvent is removed to leave the crudefree ester. This is purified by column chromatography and converted tothe hydrochloride salt by treatment with HCl in ether. The product isrecrystallised from hot ethyl acetate/methanol to yield the titlecompound.

Compounds prepared according to the methods described above weregenerally characterized by proton and/or carbon-13 NMR and/or infraredspectroscopy. Elemental analysis was obtained for compounds listed inTable 1.

Example 24 S-{(±)-trans-2-(4-morpholinyl)cyclohexyl!}naphthyl-1-thioacetate monohydrochloride(Compound #24)

1-Naphthylacetyl chloride is prepared according to the method describedin Example 8 using 1-naphthylacetic acid (2.0 g, 10.8 mmol) to give ayellow oil which is dissolved in chloroform (10 mL). This solution isadded to a solution of (±)-trans- 2-(4-morpholinyl)!cyclohexanethiol (2g, 10 mmol) in chloroform (10 mL), and the mixture is stirred at roomtemperature for 8 hours under nitrogen. The solvent is removed and theresidue is partitioned between 1M hydrochloric acid (100 mL) and ether(80 mL). The organic layer is separated and the aqueous is washed withmore ether (2×60 mL). The aqueous mixture is basified to pH>12 by theaddition of 50% sodium hydroxide solution, and extracted with ether(1×80 mL, 2×50 mL). These ether extracts of the basic aqueous solutionare washed repeatedly with water to remove any unreacted aminothiol,dried over sodium sulfate, and the solvent is removed to leave the crudefree thioester. This is converted to the hydrochloride salt bydissolving it in 1M hydrochloric acid (60 mL), adding sodium chloride(12 g), and extracting with chloroform (3×75 mL). The chloroform isremoved in vacuo and the residue is recrystallised from ethylacetate/methanol to yield the title compound.

Example 25 S-{(±)-trans-{2-bis(2-methoxyethyl)amino!cyclohexyl}}-4-bromothiobenzoatemonohydrochloride (Compound #25)

(i) The intermediate aminothiol, (±)-trans-{2-bis(2-methoxyethyl)amino!}cyclohexanethiol, is prepared by the methoddetailed in Example 23(i), refluxing bis(2-methoxyethyl)amine (13 mL, 88mmol), cyclohexene sulfide (10 g, 88 mmol) and water (8 mL).

(ii) 4-Bromobenzoyl chloride (2.4 g, 11 mmol) in chloroform (10 mL) isadded to a solution of (±)-trans-{2-bis(2-methoxyethyl)amino!}cyclohexanethiol (2 g, 10 mmol) in chloroform(10 mL), and the mixture is stirred at room temperature for 8 hoursunder nitrogen. The crude free thioester is obtained using the work-upprocedure described in Example 24, and is converted to the hydrochloridesalt by dissolving it in 1M hydrochloric acid (60 mL), adding sodiumchloride (12 g), and extracting with chloroform (3×75 mL). Thechloroform is removed in vacuo and the residue is recrystallised fromethyl acetate/methanol to yield the title compound.

Example 26 (±)-trans-2-(diisopropylamino)cyclohexyl!acenaphthene-1-carboxylatemonohydrochloride (Compound #26)

(i) The intermediate aminoalcohol,(±)-trans-(2-diisopropylamino)cyclohexanol, is prepared by the methoddetailed in Example 1(i), refluxing diisopropylamine (22.3 mL, 170mmol), cyclohexene oxide (17.2 mL, 170 mmol) and water (8 mL) for 30hours. The crude product is purified by fill vacuum distillation.

(ii) Acenaphthene-1-carboxylic acid (2.28 g, 11.5 mmol) is preparedaccording to the method described by P. R. Halfpenny et al. inSynthesis, 1990, 517-519 or in U.S. Pat. Nos. 4,906,655 and 5,019,588.It is converted to the corresponding acid chloride according to themethod described in Example 8, and is dissolved in chloroform (10 mL)and refluxed under nitrogen with a solution of(±)-trans-(2-diisopropylamino)cyclohexanol (2.2 g, 11 mmol) for 20hours. The solvent is removed in vacuo, and the residue is partitionedbetween 1M hydrochloric acid (100 mL) and ether (100 mL). The etherlayer is separated and the aqueous is washed with more ether (2×50 mL),and then basified by the addition of 50% sodium hydroxide solution. Thisis then extracted with ether (4×40 mL), and the combined ether extractsare washed repeatedly with water to remove any unreacted aminoalcohol.The ether containing the product is then dried over sodium sulfate, andthe solvent is removed to leave the crude free ester. The free ester isconverted to the hydrochloride salt by treatment with HCl in ether. Theresulting solid is washed with ether and recrystallised from hotacetate/methanol to yield the title compound.

Example 27 (±)-trans- 2-(4-morpholinyl)cyclohexyl!diphenylacetatemonohydrochloride (Compound #27)

A solution of diphenylacetylchloride (2.95 g, 128 mmol) in chloroform(10 mL) is slowly added to a solution of (±)-trans-2-(4-morpholinyl)!cyclohexanol prepared as in Example 4(i) (2.25 g, 12.2mmol) in chloroform (10 mL) under nitrogen. The mixture is refluxed for14 hours, and the crude ester is obtained using the work-up proceduredescribed in Example 26. It is dissolved in ether (40 mL) anddichloromethane (5 mL) and treated with HCl in ether to precipitate thesalt, which is washed with ether and recrystallised from ethylacetate/methanol to yield the title compound.

Example 28 (±)-trans-2-(4-morpholinyl)cyclohexyl!-3-trifluoromethylbenzoate monohydrochloride(Compound #28)

3-(Trifluoromethyl)benzoylchloride (2.96 g, 14.2 mmol), is dissolved inchloroform (15 mL) and is refluxed for 60 hours with a solution of(±)-trans- 2-(4-morpholinyl)!cyclohexanol (2.5 g, 13.5 mmol) inchloroform (12 mL) under nitrogen. The solvent is removed in vacuo, andthe residue is treated as in Example 26 to give the crude free ester.This is purified by column chromatography using silica gel andchloroform/ethyl acetate (9:1) as eluent. The free ester is converted tothe salt by treatment with HCl in ether. The resulting solid is washedwith ether and recrystallised from hot ethyl acetate/methanol to yieldthe title compound.

Example 29 7-(1-pyrrolidinyl)-1-oxaspiro 4.5!dec-8-yl!naphthyl-1-acetatemonohydrochloride (Compound #29)

(i) 7-Pyrrolidinyl)-1-oxaspiro 4.5!decan-8-ol is prepared by the methoddescribed in Example I(i), refluxing the corresponding epoxide (5 g, 32mmol, prepared according to the method described in U.S. Pat. No.4,737,493) with pyrrolidine (2.28 g, 32 mmol) and water (5 mL) undernitrogen until GC or tlc analysis show the reaction to be complete. Theproduce is purified by full vacuum distillation.

(ii) The title compound is prepared according to the method described inExample 8 using 1-naphthylacetic acid (2 g, 10.8 mmol) and7-(pyrrolidinyl)-1-oxaspiro 4.5!decan-8-ol (2.25 g, 10 mmol). Thesolvent is removed in vacuo, and the residue is treated as in Example 8to leave the crude free ester. This is dissolved in ether (40 mL) anddichloromethane (5 mL) and treated with HCl in ether to precipitate thesalt. It is washed with ether and recrystallised from ethylacetate/methanol to yield the title compound.

                                      TABLE 1    __________________________________________________________________________    Compound           Formula Calculated  Found    __________________________________________________________________________    #1     C.sub.18 H.sub.24 NO.sub.3 Cl.sub.3                   C 52.89, H 5.92, N 3.43%                               C 52.59, H 5.78, N 3.37%    #3     C.sub.22 H.sub.30 NO.sub.3 Cl.sub.3                   C 57.09, H 6.53, N 3.03%                               C 57.05, H 6.31, N 3.08%    #4     C.sub.18 H.sub.24 NO.sub.4 Cl.sub.3                   C 50.90, H 5.70, N 3.30%                               C 50.88, H 5.70, N 3.25%    #5     C.sub.20 H.sub.28 NO.sub.3 Cl.sub.3                   C 54.99, H 6.46, N 3.21%                               C 54.31, H 6.49, N 3.26%    #6     C.sub.20 H.sub.26 NO.sub.3 ClS                   C 60.67, H 6.62, N 3.54%                               C 60.69, H 6.57, N 3.58%    #7     C.sub.18 H.sub.32 NO.sub.2 Cl                   C 65.53, H 9.78, N 4.25%                               C 65.78, N 9.84, N 4.42%    #8     C.sub.22 H.sub.28 NO.sub.3 Cl                   C 67.77, H 7.24, N 3.59%                               C 67.47, H 7.21, N 3.57%    #9     C.sub.22 H.sub.28 NO.sub.3 Cl                   C 67.77, H 7.24, N 3.59%                               C 67.60, H 7.25, N 3.66%    #10    C.sub.18 H.sub.26 NO.sub.3 Cl                   C 63.61, H 7.71, N 4.12%                               C 63.50, H 7.56, N 4.17%    #11    C.sub.18 H.sub.24 NO.sub.3 Cl.sub.3                   C 52.89, H 5.92, N 3.43%                               C 52.75, H 5.90, N 3.40%    #12    C.sub.18 H.sub.25 N.sub.2 O.sub.5 Cl                   C 56.18, H 6.55, N 7.28%                               C 55.85, H 6.48, N 7.20%    #13    C.sub.23 H.sub.32 N.sub.2 O.sub.2 Cl.sub.2                   C 62.87, H 7.34, N 6.38%                               C 62.65, H 7.22, N 6.28%    #14    C.sub.23 H.sub.31 N.sub.2 O.sub.2 Cl                   C 68.56, H 7.75, N 6.95%                               C 67.63, H 7.52, N 6.91%    #15    C.sub.21 H.sub.26 NO.sub.3 Cl                   C 67.10, H 6.97, N 3.73%                               C 67.17, H 6.90, N 3.78%    #16    C.sub.20 H.sub.26 NO.sub.3 ClS                   C 60.67, H 6.62, N 3.54%                               C 60.40, H 6.53, N 3.51%    #17    C.sub.18 H.sub.25 NO.sub.3 ClBr                   C 51.63, H 6.02, N 3.34%                               C 51.56, H 6.01, N 3.34%    #18    C.sub.19 H.sub.24 NO.sub.3 Cl.sub.3                   C 54.24, H 5.75, N 3.33%                               C 54.33, H 5.78, N 3.32%    __________________________________________________________________________

Example 30 Assessment of Antiarrhythmic Efficacy

Antiarrhythmic efficacy was assessed by investigating the effect of acompound on the incidence of cardiac arrhythmias in conscious ratssubject to coronary artery occlusion. Rats weighing 200-300 gms weresubjected to preparative surgery and assigned to groups in a randomblock design. In each case, the animal was anesthetized with halothaneduring surgical preparation. The left femoral artery was cannulated formeasurement of mean arterial blood pressure and withdrawal of bloodsamples. The left femoral vein was also cannulated for injection ofdrugs. The thoracic cavity was opened and a polyethylene occluderloosely placed around the left anterior descending coronary artery. Thethoracic cavity was then closed. ECG was recorded by insertion ofelectrodes placed along the anatomical axis of the heart. All cannulaeand electrode leads were exteriorized in the mid scapular region. Inrandom and double-blind manner, about 0.5 to 2 hours post-surgery, aninfusion of vehicle, or the compound to be tested was given. After 15minutes infusion, the occluder was pulled so as to produce coronaryartery occlusion. ECG, arrhythmias, blood pressure, heart rate andmortality were monitored for 30 minutes after occlusion. Arrhythmiaswere recorded as ventricular tachycardia (VT) and ventricularfibrillation (VF) and scored according to Curtis, M. J. and Walker, M.J. A., Cardiovasc. Res. 22:656 (1988) (see Table 2).

                  TABLE 2    ______________________________________    Score         Description    ______________________________________    0    0-49 VPBs    1    50-499 VPBs    2    >499 VPBs and/or 1 episode of spontaneously reverting VT or VF    3    >1 episode of VT or VF or both (<60s total combined duration)    4    VT or VF or both (60-119s total combined duration)    5    VT or VF or both (>119s total combined duration)    6    fatal VF starting at >15 min after occlusion    7    fatal VF starting at between 4 min and 14 min 59s after occlusion    8    fatal VF starting at between 1 min and 3 min 59s after occlusion    9    fatal VF starting <1 min after occlusion    ______________________________________

Where:

VPB=ventricular premature beats

VT=ventricular tachycardia

VF=ventricular fibrillation

Rats were excluded from the study if they did not exhibit pre-occlusionserum potassium concentrations within the range of 2.9-3.9 mM. Occlusionis associated with increases in R-wave height and "S-T" segmentelevation; and an occluded zone (measured after death by cardiogreen dyeperfusion) in the range of 25%-50% of total left-ventricular weight.

Table 3 describes the result of tests of the compounds described thereinas values of arrhythmia score at a given dose in micromoles/kg/min.

                  TABLE 3    ______________________________________    Compound         Dose   AS    ______________________________________    Vehicle                 7    #2               20     4    #4               5      3.6    #5               4      3    #6               5      1.8    #8               2      3    #9               4      1.3    #10              10     2.2    #12              8      3    #15              12     2    #16              8      0.3    ______________________________________

Example 31 Measurement of ECG Parameters

Rats weighing 200-250 gms were used in this example. Animals wereanesthetized with 60 mg/kg pentobarbitone i.p. The carotid artery andjugular vein were cannulated for measurement of blood pressure and druginjection, respectively. ECG was recorded by insertion of electrodesplaced along the anatomical axis of the heart. All compounds were givenas bolus injections.

Various ECG parameters were measured. The most sensitive of these formeasuring sodium channel blockade is RSh (J. Pharmacology Methods27:51-58 (1992)). Table 4 describes the results of the tests as ED₂₅(micromoles/kg) which are the doses required to produce a 25% increasein the parameter measured (ne=not estimated). The increases in P-Rinterval, QRS interval and RSh indicate cardiac sodium channel blockadewhile the increase in Q-T interval indicates ancillary cardiac potassiumchannel blockade which is the property of a type 1a antiarrhythmic.

                  TABLE 4    ______________________________________    Compound     RSh    PR         QRS  QT    ______________________________________    #1           10     17         ne   78    #2           11     23         ne   53    #3           140    140        130  160    #4           10     44         ne   ne    #5           36     43         66   45    #6           100    ne         ne   79    #7            6     84         ne   41    #8           11     20         42   57    #9           13     ne         ne   20    #10          16     ne         ne   25    #12          17     64         82   44    #15          80     340        90   ne    #16          23     230        690  33    ______________________________________

Example 32 Assessment of Sodium Channel Blockade

Rats were prepared according to the preceding procedure. Two silverstimulating electrodes were inserted through the chest wall andimplanted in the left ventricle. Square wave stimulation was used todetermine threshold current for capture, ventricular fibrillationthreshold current, and effective refractory period (Howard, P. G. andWalker, M. J. A., Proc. West. Pharmacol. Soc. 33:123-127 (1990)). Table5 contains ED₂₅ values for these indices of cardiac sodium channelblockade, where the ED₂₅ is the infusion rate in micromoles/kg/minute ofcompound required to elicit a 25% increase from control. The increasesin refractoriness indicate ancillary blockade of potassium channels. Thethreshold current for capture is represented by "iT". The fibrillationthreshold current is represented by "VFT". The effective refractingperiod is represented by "ERP".

                  TABLE 5    ______________________________________    Compound   iT            VFT    ERP    ______________________________________    #1         6             3      4    #2         5             2      3    #5         5             4      4    #6         12            9      7    #8         5             2      4    #9         34            7      8    #10        15            11     8    #12        4             5      6    #15        33            18     20    #16        15            2      5    ______________________________________

EXAMPLE 33 Voltage Clamp Tests

In order to directly measure cardiac sodium channel blockade, standardwhole cell voltage clamp tests were carried out using single isolatedadult rat cardiac cells. Results in the form of EC₅₀ values, which aremicromolar concentrations required to produce a 50% reduction in sodiumcurrent, are presenteed in Table 6.

                  TABLE 6    ______________________________________           Compound    ______________________________________           #1      200           #2      50           #3      >150           #4      >500           #6      150           #8      80           #9      >100           #10     >300           #12     >300           #15     ne           #16     225    ______________________________________

Example 34 Nerve Conduction Blockade

In order to establish the potency of the compounds to block nerveconduction, two in vitro assays were used. The first was the phrenicnerve diaphragm of the rat. The second was the hypogastric nerve vasdeferens. Nerve blockade in these preparations is indicative of localanesthetic activity. Compounds were administer to the bath solution inincreasing concentrations while the preparations were being stimulatedwith regular electrical impulses. Table 7 shows the micromolarconcentrations at which the twitch response from electrical stimulationis reduced to 50% of control value.

                  TABLE 7    ______________________________________                  Compound                  #1    #2     #3     #5    #6    ______________________________________    Phrenic nerve diaphragm                    90      120    200  180    30    Hypogastric nerve vas deferens                    40       25    300  100   100    ______________________________________

Example 35 Opioid-like Effects

During in vivo tests of compound #6, it was observed that this compoundinduced opioid-like effects on the central nervous system of the rat.These effects were completely blocked by naloxone, an inhibitor of mu,delta and kappa opioid agonists. This provides evidence that some of thecompounds may have analgesic activity through activation of opioidreceptors. Examination of members of this series of compounds byanalgesic assays and binding studies show the presence of opioid bindingand activity.

From the foregoing, it will be evident that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

We claim:
 1. An enantiomer or geometric isomer of a compound of formulaI, or a solvate or pharmaceutically acceptable salt thereof, saidcompound of the formula: ##STR45## wherein X is a direct bond; or--(CH₂)_(n) --Y--, where n=1, 2, or 3, and Y is a direct bond, O or S;or--CH(R₁₂)--Y--, where R₁₂ is alkyl of from one to six carbon atoms, asaturated carbocyclic ring of from three to six carbon atoms, phenyl orbenzyl, and Y is a direct bond, O or S; or --C(R₁₃ )═CH--, where R₁₃ ishydrogen, alkyl of from one to six carbon atoms, or phenyl; R₁ and R₂,taken together with the nitrogen atom to which they are attached, formasaturated monoloyclic nitrogen heterocyclic ring of five to eight ringatoms, containing only carbon, nitrogen and oxygen ring atoms, and saidheterocyclic ring containing not more than two nitrogen ring atoms, thesecond nitrogen being optionally substituted with an alkyl group of oneto six carbon atoms or a phenyl ring; R₃ and R₄ are independentlyattached to the cyclohexane ring at the 3-, 4-, 5-, or 6-positions, andare independently hydrogen, hydroxy, alkyl of one to six carbon atoms oralkoxy of one to six carbon atoms, or are points of attachment of aspiro five- or six-membered heterocyclic ring containing one oxygen orsulfur atom; and A is an alkyl group of five to twelve carbon atoms, oris a saturated carbocyclic ring of three to six carbon atoms, or isselected from formulae III, IV, V, VI, VII or VIII: ##STR46## where R₅,R₆ and R₇ are independently hydrogen, hydroxy, amino, fluorine,chlorine, bromine, nitro, trifluoromethyl, alkyl of one to six carbonatoms, alkoxy of one to six carbon atoms, or aryl, and when X is adirect bond at least one of R₅, R₆ and R₇ is a hydroxy, fluorine,chlorine, bromine, trifluoromethyl, alkyl of from one to six carbonatoms, or aryl substituent, and when X is --CH═CH--, and R₁ and R₂ whentaken together with the nitrogen atom to which they are attached, form aN-phenylpiperazine ring, and R₃ and R₄ are hydrogen, at least one of R₅,R₆ and R₇ is a substituent other than hydrogen; ##STR47## where R₈ andR₉ hydroxy, fluorine, chlorine, bromine, alkyl of one to six carbonatoms, alkoxy of one to six carbon atoms or aryl; ##STR48## where R₈ andR₉ are define as above; ##STR49## where R₁₀ is hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of from one to six carbon atoms,alkoxy of from one to six carbon atoms or aryl; Z is CH₂, O, S, orN--R₁₁ where R₁₁ is hydrogen or alkyl of one to six carbon atoms;##STR50## only when X is a direct bond; ##STR51## only when X is adirect bond.
 2. An enantiomer or geometric isomer of a compound offormula I, or a solvate or pharmaceutically acceptable salt thereof,said compound of the formula: ##STR52## wherein X is a direct bond; or--(CH₂)_(n) --Y--, where n=1 and Y is a direct bond, O or S;or--CH(R₁₂)--, where R₁₂ is alkyl of from one to six carbon atoms; or--C(R₁₃)═CH--, where R₁₃ is hydrogen; R₁ and R₂ are defined as in claim1; R₃ and R₄ are defined as in claim 1; and A is defined as in claim 1;with the proviso that, when X is --(CH₂)_(n) --Y--, and n=1, and Y is adirect bond, and R₁ and R₂, when taken together with the nitrogen atomto which they are attached, form a pyrrolidinyl ring, and R₃ and R₄ arehydrogen, A may not be 4-thianaphthenyl.
 3. An enantiomer or geometricisomer of a compound of formula I, or a solvate or pharmaceuticallyacceptable salt thereof, said compound of the formula: ##STR53## whereinX is --(CH₂)_(n) --Y--, where n=1 and Y is a direct bond or O;or--CH(R₁₂)--, where R₁₂ is alkyl of from one to six carbon atoms; R₁ andR₂ are defined as in claim 1; R₃ and R₄ are independently attached tothe cyclohexane ring at the 4- or 5-positions, and are independentlyhydrogen, alkoxy of one to six carbon atoms, or are points of attachmentof a spiro five- or six-membered heterocyclic ring containing one oxygenatom; and A is an alkyl group of five to twelve carbon atoms, or is asaturated carbocyclic ring of three to six carbon atoms, or is selectedfrom:formula III where R₅, R₆ and R₇ are independently hydrogen,hydroxy, amino, fluorine, chlorine, bromine, nitro, trifluoromethyl,alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms, oraryl; or formula IV where R₈ and R₉ are independently hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of one to six carbon atoms, alkoxy ofone to six carbon atoms or aryl; or formula V where R₈ and R₉ aredefined as above; or formula VI where R₁₀ is hydrogen, hydroxy,fluorine, chlorine, bromine, alkyl of from one to six carbon atoms,alkoxy of from one to six carbon atoms, or aryl; Z is CH₂, O, S, orN--R₁₁ where R₁₁ is hydrogen or alkyl of one to six carbon atoms; withthe proviso that, when X is --(CH₂)_(n) --Y--, and n=1, and Y is adirect bond, and R₁ and R₂, when taken together with the nitrogen atomto which they are attached, form a pyrrolidinyl ring, and R₃ and R₄ arehydrogen, A may not be 4-thianaphthenyl.
 4. A method for treatingarrhythmia comprising administering to a warm-blooded animal aneffective amount of an enantiomer or geometric isomer of a compound offormula IX, or a solvate or pharmaceutically acceptable salt thereof,said compound of the formula: ##STR54## wherein R₁ and R₂ are defined asin claim 1; R₃ and R₄ are independently attached to the cyclohexane ringat the 4- or 5- positions, and are independently hydrogen, methoxy, orare points of attachment of a five-membered oxaspiran ring; andA is asaturated carbocyclic ring of three to six carbon atoms, or is selectedfrom:formula III where R₅ is hydrogen, and R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, methyl, ethyl, methoxy, or ethoxy, and at least one ofR₆ and R₇ is a substituent other than hydrogen; or formula IV where R₈and R₉ are hydrogen; or formula V where R₈ R₉ are hydrogen; or formula Vwhere R₈ and R₉ are hydrogen; or formula VI where R₁₀ is hydrogen, and Zis CH₂, O, S, or N--R₁₁ where R₁₁ is hydrogen or methyl.
 5. Anenantiomer or geometric isomer of a compound of formula X, or a solvateor pharmaceutically acceptable salt thereof, said compound of theformula: ##STR55## wherein R₁ and R₂ are defined as in claim 4; R₃ andR₄ are defined as in claim 4; andA is a saturated carbocyclic ring offrom three to six carbon atoms, or is selected from:formula III where R₅is hydrogen, and R₆ and R₇ are independently hydrogen, hydroxy, amino,fluorine, chlorine, bromine, nitro, trifluoromethyl, methyl, ethyl,methoxy, or ethoxy, and at least one of R₆ and R₇ is a substituent otherthan hydrogen; or formula IV where R₈ and R₉ are hydrogen; or formula Vwhere R₈ and R₉ are hydrogen; or formula VI where R₁₀ is hydrogen, and Zis CH₂, O, S, or N--R₁₁ where R₁₁ is hydrogen or methyl; with theproviso that when R₁ and R₂, taken together with the nitrogen atom towhich they are attached, form a pyrrolidinyl ring, and R₃ and R₄ arehydrogen, A may not be 4-thianaphthenyl.
 6. An enantiomer or geometricisomer of a compound of formula XIII, or a solvate or pharmaceuticallyacceptable salt thereof, said compound of the formula: ##STR56## whereinX is a direct bond, trans-CH═CH--, --CH₂ -- or --CH₂ --O--;R₁ and R₂ aredefined as in claim 1; and A is selected from cyclohexyl,3,4-dichlorophenyl, 4-bromophenyl, 1-naphthyl, 2-naphthyl or3-thianaphthenyl.
 7. An enantiomer or geometric isomer of a compound offormula XIV, or a solvate or pharmaceutically acceptable salt thereof,said compound of the formula: ##STR57## wherein X is a direct bond; R₁and R₂, taken together with the nitrogen atom to which they areattached, forma saturated monocyclic nitrogen heterocyclic ring of fiveto eight ring atoms, containing only carbon, nitrogen and oxygen ringatoms, and said heterocyclic ring containing not more than two nitrogenring atoms, the second nitrogen being optionally substituted with analkyl group of one to six carbon atoms or a phenyl ring; R₃ and R₄ areindependently attached to the cyclohexane ring at the 3-, 4-, 5-, or6-positions, and are independently hydrogen, hydroxy, alkyl of one tosix carbon atoms or alkoxy of one to six carbon atoms, or are points ofattachment of a spiro five- or six-membered heterocyclic ring containingone oxygen or sulfur atom; and A is an alkyl group of five to twelvecarbon atoms, or is a saturated carbocyclic ring of three to six carbonatoms, or is selected from formulae III, IV, V, VI, VII or VIII:##STR58## where R₅, R₆ and R₇ are independently hydrogen, hydroxy,amino, fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of oneto six carbon atoms, alkoxy of one to six carbon atoms, or aryl, andwhen X is a direct bond at least one of R₅, R₆ and R₇ is a substituentother than hydrogen; ##STR59## where R₈ and R₉ are independentlyhydroxy, fluorine, chlorine, bromine, alkyl of one to six carbon atoms,alkoxy of one to six carbon atoms or aryl; ##STR60## where R₈ and R₉ aredefined as above; ##STR61## where R₁₀ is hydrogen, hydroxy, fluorine,chlorine, bromine, alkyl of from one to six carbon atoms, alkoxy of fromone to six carbon atoms, or aryl; Z is CH₂, O, S, or N--R₁₁ where R₁₁ ishydrogen or alkyl of one to six carbon atoms; ##STR62## only when X is adirect bond; ##STR63## only when X is a direct bond.
 8. An enantiomer orgeometric isomer of a compound of formula XIV, or a solvate orpharmaceutically acceptable salt thereof, said compound of the formula:##STR64## wherein X is a direct bond; R₁ and R₂ are defined as in claim7;R₃ and R₄ are independently attached to the cyclohexane ring at the 4-or 5- positions, and are independently hydrogen, alkoxy of one to sixcarbon atoms, or are points of attachment of a spiro five- orsix-membered heterocyclic ring containing one oxygen atom; and A isdefined as in claim
 7. 9. A method for treating arrhythmia comprisingadministering to a warm-blooded animal an effective amount of anenantiomer or geometric isomer of a compound of formula XV, or a solvateor pharmaceutically acceptable salt thereof, said compound of theformula: ##STR65## wherein X is a --CH₂ -- or --CH₂ --O--; R₁ and R₂ aredefined as in claim 7;R₃ and R₄ are independently attached to thecyclohexane ring at the 4- or 5- positions, and are independentlyhydrogen, methoxy, or are points of attachment of a five-memberedoxaspiran ring; and A is a saturated carbocyclic ring of from three tosix carbon atoms, or is selected from:formula III where R₅ is hydrogen,and R₆ and R₇ are independently hydrogen, hydroxy, fluorine, chlorine,bromine, nitro, trifluoromethyl, methyl, ethyl, methoxy, or ethoxy; orformula IV where R₈ and R₉ are hydrogen; or formula V where R₈ and R₉are hydrogen; or formula VI where R₁₀ is hydrogen, and Z is CH₂, O, S,or N--R₁₁ where R₁₁ is hydrogen or methyl.
 10. A composition comprisinga compound according to any one of claims 1-3, 5 and 6-9 in combinationwith a pharmaceutically acceptable carrier or diluent.
 11. A method forblocking sodium or potassium ion channels in vitro comprising contactinga preparation containing sodium or potassium ion channels with aneffective amount of a compound according to any one of claims 1-3, 5 and6.
 12. A method for blocking sodium or potassium ion channels in apatient in need thereof comprising administering to said patient aneffective amount of a compound according to any one of claims 1-3, 5 and6.
 13. A method for blocking sodium or potassium ion channels in vitrocomprising contacting a preparation containing sodium or potassium ionchannels with an effective amount of a compound according to any one ofclaims 7-8.
 14. A method for blocking sodium or potassium ion channelsin a patient in need thereof comprising administering to said patient aneffective amount of a compound according to any one of claims 7-8.
 15. Amethod for treating arrhythmia comprising administering to awarm-blooded animal an effective amount of an enantiomer or geometricisomer of a compound of formula I, or a solvate or pharmaceuticallyacceptable salt thereof, said compound of the formula: ##STR66## whereinX is a direct bond; R₁ and R₂ are defined as in claim 1;R₃ and R₄ aredefined as in claim 1; and A is an alkyl group of five to twelve carbonatoms, or is a saturated carbocyclic ring of three to six carbon atoms,or is selected from formulae III, IV, V, VI, VII or VIII: ##STR67##where R₅, R₆ and R₇ are independently hydrogen, hydroxy, amino,fluorine, chlorine, bromine, nitro, trifluoromethyl, alkyl of one to sixcarbon atoms, alkoxy of one to six carbon atoms, or aryl; ##STR68##where R₈ and R₉ are independently, hydroxy, fluorine, chlorine, bromine,alkyl of one to six carbon atoms, alkoxy of one to six carbon atoms oraryl; ##STR69## where R₈ and R₉ are defined as above; ##STR70## whereR₁₀ is hydrogen, hydroxy, fluorine, chlorine, bromine, alkyl of from oneto six carbon atoms, alkoxy of from one to six carbon atoms, or aryl; Zis CH₂, O, S, or N--R₁₁ where R₁₁ is hydrogen or alkyl of one to sixcarbon atoms; ##STR71## only when X is a direct bond; ##STR72## onlywhen X is a direct bond.
 16. A method for treating arrhythmia comprisingadministering to a warm-blooded animal an effective amount of anenantiomer or geometric isomer of a compound of formula XIV, or asolvate or pharmaceutically acceptable salt thereof, said compound ofthe formula: ##STR73## wherein X is a direct bond; or --(CH₂)_(n) --Y--,where n=1, 2, or 3, and Y is a direct bond, O or S;or --CH(R₁₂)--Y--,where R₁₂ is alkyl of from one to six carbon atoms, a saturatedcarbocyclic ring of from three to six carbon atoms, phenyl or benzyl,and Y is a direct bond, O or S; or --C(R₁₃)═CH--, where R₁₃ is hydrogen,alkyl of from one to six carbon atoms, or phenyl; R₁ and R₂ are definedas in claim 7; R₃ and R₄ are defined as in claim 10; and A is an alkylgroup of five to twelve carbon atoms, or is a saturated carbocyclic ringof three to six carbon atoms, or is selected from formulae III, IV, V,VI, VII or VIII: ##STR74## where R₅, R₆ and R₇ are independentlyhydrogen, hydroxy, amino, fluorine, chlorine, bromine, nitro,trifluoromethyl, alkyl of one to six carbon atoms, alkoxy of one to sixcarbon atoms, or aryl; ##STR75## where R₈ and R₉ are independentlyhydrogen, hydroxy, fluorine, chlorine, bromine, alkyl of one to sixcarbon atoms, alkoxy of one to six carbon atoms or aryl; ##STR76## whereR₈ and R₉ are defined as above; ##STR77## where R₁₀ is hydrogen,hydroxy, fluorine, chlorine, bromine, alkyl of from one to six carbonatoms, alkoxy of from one to six carbon atoms, or aryl; Z is CH₂, O, S,or N--R₁₁ where R₁₁ is hydrogen or alkyl of one to six carbon atoms;##STR78## only when X is a direct bond; ##STR79## only when X is adirect bond.